Piperazine-piperidines with CXCR3 antagonist activity

ABSTRACT

The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: 
                         
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the various moieties are defined herein. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, xenograft rejection), infectious diseases (e.g, tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.

REFERENCE TO PRIORITY APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/653,378 filed on Feb. 16, 2005, which is incorporated herein inits entirety by reference.

FIELD OF THE INVENTION

The present invention relates to novel pyridyl and phenyl substitutedpiperazine-piperidines with CXCR3 antagonist activity, pharmaceuticalcompositions containing one or more such antagonists, one or more suchantagonists in combination with other compounds with chemokine activity,one or more such antagonists in combination with known immunosuppressiveagents, non-limiting example(s) include Methotrexate, interferon,cyclosporin, FK-506 and FTY720, methods of preparing such antagonistsand methods of using such antagonists to modulate CXCR3 activity. Thisinvention also discloses methods of using such CXCR3 antagonists for thetreatment (non-limiting examples include palliative, curative andprophylactic therapies) of diseases and conditions where CXCR3 has beenimplicated. Diseases and conditions where CXCR3 has been implicatedinclude but are not limited to inflammatory conditions (psoriasis andinflammatory bowel disease), autoimmune disease (multiple sclerosis,rheumatoid arthritis), fixed drug eruptions, cutaneous delayed-typehypersensitivity responses, type I diabetes, viral meningitis andtuberculoid leprosy. CXCR3 antagonist activity has also been indicatedas a therapy for tumor growth suppression as well as graft rejection(allograft and zenograft rejections for example).

BACKGROUND OF THE INVENTION

Chemokines constitute a family of small cytokines that are produced ininflammation and regulate leukocyte recruitment (Baggiolini, M. et al.,Adv. Immunol., 55: 97-179 (1994); Springer, T. A., Annu. Rev. Physio.,57: 827-872 (1995); and Schall, T. J. and K. B. Bacon, Curr. Opin.Immunol, 6: 865-873 (1994)). Chemokines are capable of selectivelyinducing chemotaxis of the formed elements of the blood (other than redblood cells), including leukocytes such as neutrophils, monocytes,macrophages, eosinophils, basophils, mast cells, and lymphocytes, suchas T cells and B cells. In addition to stimulating chemotaxis, otherchanges can be selectively induced by chemokines in responsive cells,including changes in cell shape, transient rises in the concentration ofintracellular free calcium ions ([Ca²⁺]_(i)), granule exocytosis,integrin upregulation, formation of bioactive lipids (e.g.,leukotrienes) and respiratory burst, associated with leukocyteactivation. Thus, the chemokines are early triggers of the inflammatoryresponse, causing inflammatory mediator release, chemotaxis andextravasation to sites of infection or inflammation.

The chemokines are related in primary structure and share four conservedcysteines, which form disulfide bonds. Based upon this conservedcysteine motif, the family can be divided into distinct branches,including the C—X—C chemokines (α-chemokines) in which the first twoconserved cysteines are separated by an intervening residue (e.g., IL-8,IP-10, Mig, I-TAC, PF4, ENA-78, GCP-2, GROα, GROβ, GROδ, NAP-2, NAP-4),and the C—C chemokines (β-chemokines), in which the first two conservedcysteines are adjacent residues (e.g., MIP-1α, MIP-1β, RANTES, MCP-1,MCP-2, MCP-3, I-309) (Baggiolini, M. and Dahinden, C. A., ImmunologyToday, 15:127-133 (1994)). Most CXC-chemokines attract neutrophilleukocytes. For example, the CXC-chemokines interleukin 8 (IL-8), GROalpha (GROα), and neutrophil-activating peptide 2 (NAP-2) are potentchemoattractants and activators of neutrophils. The CXC-chemokinesdesignated Mig (monokine induced by gamma interferon) and IP-10(interferon-gamma inducible 10 kDa protein) are particularly active ininducing chemotaxis of activated peripheral blood lymphocytes.CC-chemokines are generally less selective and can attract a variety ofleukocyte cell types, including monocytes, eosinophils, basophils, Tlymphocytes and natural killer cells. CC-chemokines such as humanmonocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES(Regulated on Activation, Normal T Expressed and Secreted), and themacrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β) have beencharacterized as chemoattractants and activators of monocytes orlymphocytes, but do not appear to be chemoattractants for neutrophils.

A chemokine receptor that binds the CXC-chemokines IP-10 and Mig hasbeen cloned and characterized (Loetscher, M. et al., J. Exp. Med., 184:963-969 (1996)). CXCR3 is a G-protein coupled receptor with seventransmembrane-spanning domains and has been shown to be restrictivelyexpressed in activated T cells, preferentially human Th1 cells. Onbinding of the appropriate ligand, chemokine receptors transduce anintracellular signal through the associated G-protein resulting in arapid increase in intracellular calcium concentration.

The receptor mediates Ca²⁺ (calcium ion) mobilization and chemotaxis inresponse to IP-10 and Mig. CXCR3 expressing cells show no significantresponse to the CXC-chemokines IL-8, GROα, NAP-2, GCP-2 (granulocytechemotactic protein-2), ENA78 (epithelial-derived neutrophil-activatingpeptide 78), PF4 (platelet factor 4), or the CC-chemokines MCP-1, MCP-2,MCP-3, MCP-4, MIP-1α, MIP-1β, RANTES, I309, eotaxin or lymphotactin.Moreover, a third ligand for CXCR3, I-TAC (Interferon-inducible T cellAlpha Chemoattractant), has also been found to bind to the receptor withhigh affinity and mediate functional responses (Cole, K. E. et al., J.Exp. Med., 187: 2009-2021 (1998)).

The restricted expression of human CXCR3 in activated T lymphocytes andthe ligand selectivity of CXCR3 are noteworthy. The human receptor ishighly expressed in IL-2 activated T lymphocytes, but was not detectedin resting T lymphocytes, monocytes or granulocytes (Qin, S. et al., J.Clin. Invest., 101: 746-754 (1998)). Additional studies of receptordistribution indicate that it is mostly CD3⁺ cells that express CXCR3,including cells which are CD95⁺, CD45RO⁺, and CD45RA^(low), a phenotypeconsistent with previous activation, although a proportion of CD20⁺ (B)cells and CD56⁺ (NK) cells also express this receptor. The selectiveexpression in activated T lymphocytes is of interest, because otherreceptors for chemokines which have been reported to attract lymphocytes(e.g., MCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β, RANTES) are also expressedby granulocytes, such as neutrophils, eosinophils, and basophils, aswell as monocytes. These results suggest that the CXCR3 receptor isinvolved in the selective recruitment of effector T cells.

CXCR3 recognizes unusual CXC-chemokines, designated IP-10, Mig andI-TAC. Although these belong to the CXC-subfamily, in contrast to IL-8and other CXC-chemokines which are potent chemoattractants forneutrophils, the primary targets of IP-10, Mig and I-TAC arelymphocytes, particularly effector cells such as activated or stimulatedT lymphocytes and natural killer (NK) cells (Taub, D. D. et al., J Exp.Med., 177: 18090-1814 (1993); Taub, D. D. et al., J. Immunol., 155:3877-3888 (1995); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021(1998)). (NK cells are large granular lymphocytes, which lack a specificT cell receptor for antigen recognition, but possess cytolytic activityagainst cells such as tumor cells and virally infected cells.)Consistently, IP-10, Mig and I-TAC lack the ELR motif, an essentialbinding epitope in those CXC-chemokines that efficiently induceneutrophil chemotaxis (Clark-Lewis, I. et al., J. Biol. Chem. 266:23128-23134 (1991); Hebert, C. A. et al., J. Biol. Chem., 266:18989-18994 (1991); and Clark-Lewis, 1. et al., Proc. Natl. Acad. Sci.USA, 90: 3574-3577 (1993)). In addition, both recombinant human Mig andrecombinant human IP-10 have been reported to induce calcium flux intumor infiltrating lymphocytes (TIL) (Liao, F. et al., J Exp. Med, 182:1301-1314 (1995)). While IP-10 has been reported to induce chemotaxis ofmonocytes in vitro (Taub, D. D. et al., J. Exp. Med., 177: 1809-1814(1993), the receptor responsible has not been identified), human Mig andI-TAC appear highly selective, and do not show such an effect (Liao, F.et al., J. Exp. Med., 182: 1301-1314 (1995); Cole, K. E. et al., J. Exp.Med., 187: 2009-2021 (1998)). IP-10 expression is induced in a varietyof tissues in inflammatory conditions such as psoriasis, fixed drugeruptions, cutaneous delayed-type hypersensitivity responses andtuberculoid leprosy as well as tumors and in animal model studies, forexample, experimental glomerulonephritis, and experimental allergicencephalomyelitis. IP-10 has a potent in vivo antitumor effect that is Tcell dependent, is reported to be an inhibitor of angiogenesis in vivoand can induce chemotaxis and degranulation of NK cells in vitro,suggesting a role as a mediator of NK cell recruitment and degranulation(in tumor cell destruction, for example) (Luster, A. D. and P. Leder, J.Exp. Med., 178: 1057-1065 (1993); Luster, A. D. et al., J. Exp. Med.182: 219-231 (1995); Angiolillo, A. L. et al., J. Exp. Med., 182:155-162 (1995); Taub, D. D. et al., J. Immunol., 155: 3877-3888 (1995)).The expression patterns of IP-10, Mig and I-TAC are also distinct fromthat of other CXC chemokines in that expression of each is induced byinterferon-gamma (IFNδ), while the expression of IL-8 is down-regulatedby IFNδ (Luster, A. D. et al., Nature, 315: 672-676 (1985); Farber, J.M., Proc. Natl. Acad. Sci. USA, 87: 5238-5242 (1990); Farber, J. M.,Biochem. Biophys. Res. Commun., 192 (1): 223-230 (1993), Liao, F. etal., J. Exp. Med., 182: 1301-1314 (1995); Seitz, M. et al., J. Clin.Invest., 87: 463-469 (1991); Galy, A. H. M. and H. Spits, J. Immunol.,147: 3823-3830 (1991); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021(1998)).

Chemokines are recognized as the long-sought mediators for therecruitment of lymphocytes. Several CC-chemokines were found to elicitlymphocyte chemotaxis (Loetscher, P. et al., FASEB J., 8: 1055-1060(1994)), however, they are also active on granulocytes and monocytes(Uguccioni, M. et al., Eur. J. Immunol., 25: 64-68 (1995); Baggiolini,M. and C. A. Dahinden, Immunol. Today, 15: 127-133 (1994)). Thesituation is different for IP-10, Mig and I-TAC, which are selective intheir action on lymphocytes, including activated T lymphocytes and NKcells, and which bind CXCR3, a receptor which does not recognizenumerous other chemokines and which displays a selective pattern ofexpression.

In view of these observations, it is reasonable to conclude that theformation of the characteristic infiltrates in inflammatory lesions,such as, for example, delayed-type hypersensitivity lesions, sites ofviral infection and certain tumors is a process mediated via CXCR3 andregulated by CXCR3 expression. Lymphocytes, particularly T lymphocytes,bearing a CXCR3 receptor as a result of activation can be recruited intoinflammatory lesions, sites of infection and/or tumors by IP-10, Migand/or I-TAC, which can be induced locally by interferon-gamma. Thus,CXCR3 plays a role in the selective recruitment of lymphocytes,particularly effector cells such as activated or stimulated Tlymphocytes. Accordingly, activated and effector T cells have beenimplicated in a number of disease states such as graft-rejection,inflammation, rheumatoid arthritis, multiple sclerosis, inflammatorybowel disease (such as Crohn's disease and ulcerative colitis) andpsoriasis. Thus, CXCR3 represents a promising target for the developmentof novel therapeutics.

Reference is made to PCT Publication No. WO 93/10091 (Applicant: GlaxoGroup Limited, Published May 27, 1993) which discloses piperidine aceticacid derivatives as inhibitors of fibrinogen-dependent blood plateletaggregation having the formula:

An illustrative compound of that series is:

Reference is also made to PCT Publication No. WO 9/20606 (Applicant: J.Uriach & CIA. S. A., Published Apr. 29, 1999) which disclosespiperazines as platelet aggregation inhibitors having the formula:

Reference is also made to US Patent Application No. US 2002/0018776 A1(Applicant: Hancock, et al. Published Feb. 14, 2002) which disclosesmethods of treating graft rejection.

Reference is also made to PCT Publication No. WO 03/098185 A2(Applicant: Renovar, Inc., Published Nov. 27, 2003) which disclosesmethods of diagnosing and predicting organ transplant rejection bydetection of chemokines, for example, CXCR3 and CCL chemokines in urine.

Reference is also made to PCT Publication No. WO 03/082335 A1(Applicant: Sumitomo Pharmaceuticals Co. Ltd., Published Oct. 9, 2003)which discloses methods of screening a CXCR3 ligand and methods ofdiagnosing type 2 diabetes by detecting the expression dose of a CXCR3ligand in a biological sample.

Reference is also made to PCT Publication No. WO 02/085861 (Applicant:Millennium Pharmaceuticals, Inc. Published Oct. 31, 2002) whichdiscloses imidazolidine compounds and their use as CXCR3 antagonistshaving the formula:

An illustrative compound of that series is:

Reference is also made to PCT Publication No. WO 03/101970 (Applicant:SmithKline Beecham Corporation, Published Dec. 11, 2003) which disclosesimidazolium compounds and their use as CXCR3 antagonists having theformula:

An illustrative example of that series is:

Reference is also made to US Patent Application No. US 2003/0055054 A1(Applicant: Medina et al, Published Mar. 20, 2003) which disclosescompounds having the formula:

An illustrative compound of that series is:

Reference is also made to U.S. Pat. No. 6,124,319 (Applicant: MacCoss etal., issued Sep. 6, 2000) which discloses compounds useful as chemokinereceptor modulators having the formula:

Reference is also made to PCT Publication WO 03/070242 A1 (Applicant:CELLTECH R& D limited, Published Aug. 28, 2003) which disclosescompounds useful as “chemokine receptor inhibitors for the treatment ofinflammatory diseases” having the formula:

There is a need for compounds that are capable of modulating CXCR3activity. For example, there is a need for new treatments and therapiesfor diseases and conditions associated with CXCR3 such as inflammatoryconditions (psoriasis and inflammatory bowel disease), autoimmunedisease (multiple sclerosis, rheumatoid arthritis) and graft rejection(allograft and zenograft rejections for example) as well as infectiousdiseases, cancers and tumors, fixed drug eruptions, cutaneousdelayed-type hypersensitivity responses, type I diabetes, viralmeningitis and tuberculoid leprosy.

There is a need for methods of treatment or prevention or ameliorationof one or more symptoms of diseases and conditions associated withCXCR3. There is a need for methods for modulating CXCR3 activity usingthe compounds provided herein.

SUMMARY OF THE INVENTION

In its many embodiments, the invention provides novel compounds of theFormula 1:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein:

Q is N, NO, NOH or C(R⁴);

Z is N, NO, NOH or C(R²⁹);

G represents a 5 to 7 membered heteroaryl, heterocyclenyl orheterocyclyl ring containing at least one N atom as ring atom of saidheteroaryl, heterocyclenyl or heterocyclyl ring, wherein each of saidheteroaryl, heterocyclenyl or heterocyclyl ring optionally additionallycontains on the ring one or more moieties which moieties can be the sameor different, each being independently selected from the groupconsisting of N,N(→O), O, S, S(O) and S(O₂), further wherein each ofsaid heteroaryl, heterocyclenyl or heterocyclyl ring is either (i)unsubstituted, or (ii) optionally independently substituted on one ormore ring carbon atoms with one or more R⁹ substituents, andindependently on one or more ring nitrogen atoms with one or more R⁸substituents, wherein said one or more R⁹ substituents can be the sameor different, and said one or more R⁸ substituents can be the same ordifferent, further wherein said G ring is fused to ring marked a inFormula 1 via carbon atom, heteroatom or both;

R³, R⁴, and R²⁹ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkylaryl, aralkyl, —CN,CF₃, haloalkyl, cycloalkyl, halogen, hydroxyalkyl, —N═CH—(R³¹),—C(═O)N(R³⁰)₂, —N(R³⁰)₂, —OR³⁰, —SO₂(R³¹), —N(R³⁰)C(═O)N(R³⁰)₂ and—N(R³⁰)C(═O)R³¹;

the R⁸ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —(CH₂)_(q)OH,—(CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)C(═O)OR³¹, —(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹, and—(CH₂)_(q)SO₂NHR³¹;

the R⁹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,arylalkyl, alkoxy, amidinyl, aryl, cycloalkyl, cyano, heteroaryl,heterocyclyl, hydroxyl, —C(═O)N(R³⁰)₂, —C(═S)N(R³⁰)₂, —C(═O)alkyl,—(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, (CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹,—(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹,—(CH₂)_(q)SO₂NHR³¹, —N(R³⁰)₂, —N(R³⁰)S(O₂)R³¹, —N(R³⁰) C(═O)N(R³⁰)₂,—OR³⁰, —SO₂(R³¹), —SO₂N(R³⁰)₂, ═O and ═S;

the R¹⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, cycloalkyl, aryl,heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, —CO₂H,hydroxyalkyl, —C(═O)N(R³⁰)₂, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹—OR³⁰, halogen,═O, and —C(═O)R³¹;

the R¹¹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl,carboxamide, CO₂H, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —OR³⁰, halogen, ═O, and—C(═O)R³¹;

R¹² moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, —CN, —C(═O)N(R³⁰)₂,—(CH₂)_(q)OH, —(CH₂)_(q)OR³¹ and —S(O₂)R³¹;

ring D is a five to nine membered cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclenyl or heterocyclyl ring having 0-4 heteroatomsindependently selected from O, S or N, wherein ring D is unsubstitutedor optionally substituted with 1-5 independently selected R²⁰ moieties;

the R²⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl,alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl,amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio,aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl,guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl,heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy,—(CH₂)_(q)OH, (CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹,—(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹,—(CH₂)_(q)SO₂NHR³¹, -alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)N(R³⁰)₂,—C(═NR³⁰)NHR³⁰, —C(═NOH)N(R³⁰)₂, —C(═NOR³¹)N(R³⁰)₂, —C(═O)OR³⁰,—N(R³⁰)₂, —N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹,—N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)SO₂(R³¹), —N(R³⁰)C(═O)N(R³⁰)₂,—N(R³⁰)SO₂(R³¹), —N(R³⁰)S(O)₂N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂, —SR³⁰,—SO₂N(R³⁰)₂, —SO₂(R³¹), —OSO₂(R³¹), and —OSi(R³⁰)₃; or alternatively twoR²⁰ moieties are linked together to form a five or six membered aryl,cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring whereinsaid five or six membered aryl, cycloalkyl, heterocyclyl,heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ringis optionally substituted with 0-4 R²¹ moieties;

the R²¹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl,alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl,amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio,aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl,formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl,heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro,trifluoromethoxy, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂,—(CH₂)_(q)NHR³¹, —(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹,—(CH₂)_(q)NSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹, -alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰,—C(═O)N(R³⁰)₂, —C(═NR³⁰)NHR³⁰, —C(═NOH)N(R³⁰)₂, —C(═NOR³¹)N(R³⁰)₂,—C(═O)OR³⁰, —N(R³⁰)₂, —N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂,—N(R³⁰)C(═O)OR³¹, —N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)SO₂(R³¹),—N(R³⁰)C(═O)N(R³⁰)₂, —N(R³⁰)SO₂(R³¹), —N(R³⁰)S(O)₂N(R³⁰)₂, —OR³⁰,—OC(═O)N(R³⁰)₂, —SR³⁰, —SO₂N(R³⁰)₂, —SO₂(R³¹), —OSO₂(R³¹), and—OSi(R³⁰)₃;

Y is selected from the group consisting of —(CR¹³R¹³)_(r)—,—CHR¹³C(═O)—, —(CHR¹³)_(r)O—, —(CHR¹³)_(r)N(R³⁰)—, —C(═O)—, —C(═NR³⁰)—,—C(═N—OR³⁰)—, —CH(C(═O)NHR³⁰)—, CH-heteroaryl-,—C(R¹³R¹³)_(r)C(R¹³)═C(R¹³)—, —(CHR¹³)_(r)C(═O)— and—(CHR¹³)_(r)N(H)C(═O)—; or alternatively Y is cycloalkyl,heterocyclenyl, or heterocyclyl wherein the cycloalkyl, heterocyclenyl,or heterocyclyl is fused with ring D;

the R¹³ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkylaryl, cycloalkyl,alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl, —CN,—CO₂H, —C(═O)R³⁰, —C(═O)N(R³⁰)₂, —(CHR³⁰)_(q)OH, —(CHR³⁰)_(q)OR³¹,—(CHR³⁰)_(q)NH₂, —(CH R³⁰)_(q)NHR³¹, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹, —NH₂, —N(R³⁰)₂,—N(R³⁰)C(═O)N(R³⁰)₂, —N(R³⁰)SO₂(R³¹), —OH, OR³⁰, —SO₂N(R³⁰)₂, and—SO₂(R³¹);

the R³⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkylaryl, aryl,aralkyl, cycloalkyl, —CN, —(CH₂)_(q)OH, —(CH₂)_(q)Oalkyl,—(CH₂)_(q)Oalkylaryl, —(CH₂)_(q)Oaryl, —(CH₂)_(q)Oaralkyl,—(CH₂)_(q)Ocycloalkyl, —(CH₂)_(q)NH₂, —(CH₂)_(q)NHalkyl,—(CH₂)_(q)N(alkyl)₂, —(CH₂)_(q)NHalkylaryl, —(CH₂)_(q)NHaryl,—(CH₂)_(q)NHaralkyl, —(CH₂)_(q)NHcycloalkyl, —(CH₂)_(q)C(═O)NHalkyl,—(CH₂)_(q)C(═O)N(alkyl)₂, —(CH₂)_(q)C(═O)NHalkylaryl,—(CH₂)_(q)C(═O)NHaryl, —(CH₂)_(q)C(═O)NHaralkyl,—(CH₂)_(q)C(═O)NHcycloalkyl, —(CH₂)_(q)SO₂alkyl, —(CH₂)_(q)SO₂alkylaryl,—(CH₂)_(q)SO₂aryl, —(CH₂)_(q)SO₂aralkyl, —(CH₂)_(q)SO₂cycloalkyl,—(CH₂)_(q)NSO₂alkyl, —(CH₂)_(q)NSO₂alkylaryl, —(CH₂)_(q)NSO₂aryl,—(CH₂)_(q)NSO₂aralkyl, —(CH₂)_(q)NSO₂cycloalkyl, —(CH₂)_(q)SO₂NHalkyl,—(CH₂)_(q)SO₂NHalkylaryl, —(CH₂)_(q)SO₂NHaryl, —(CH₂)_(q)SO₂NHaralkyl,—(CH₂)_(q)SO₂NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;

the R³¹ moieties can be the same or different, each being independentlyselected from the group consisting of alkyl, alkylaryl, aryl, aralkyl,cycloalkyl, —(CH₂)_(q)OH, —(CH₂)_(q)Oalkyl, —(CH₂)_(q)Oalkylaryl,—(CH₂)_(q)Oaryl, —(CH₂)_(q)Oaralkyl, —(CH₂)_(q)Ocycloalkyl,—(CH₂)_(q)NH₂, —(CH₂)_(q)NHalkyl, —(CH₂)_(q)N(alkyl)₂,—(CH₂)_(q)NHalkylaryl, —(CH₂)_(q)NHaryl, —(CH₂)_(q)NHaralkyl,—(CH₂)_(q)NHcycloalkyl, —(CH₂)_(q)C(═O)NHalkyl,—(CH₂)_(q)C(═O)N(alkyl)₂, —(CH₂)_(q)C(═O)NHalkylaryl,—(CH₂)_(q)C(═O)NHaryl, —(CH₂)_(q)C(═O)NHaralkyl,—(CH₂)_(q)C(═O)NHcycloalkyl, —(CH₂)_(q)SO₂alkyl, —(CH₂)_(q)SO₂alkylaryl,—(CH₂)_(q)SO₂aryl, —(CH₂)_(q)SO₂aralkyl, —(CH₂)_(q)SO₂cycloalkyl,—(CH₂)_(q)NSO₂alkyl, —(CH₂)_(q)NSO₂alkylaryl, —(CH₂)_(q)NSO₂aryl,—(CH₂)_(q)NSO₂aralkyl, —(CH₂)_(q)NSO₂cycloalkyl, —(CH₂)_(q)SO₂NHalkyl,—(CH₂)_(q)SO₂NHalkylaryl, —(CH₂)_(q)SO₂NHaryl, —(CH₂)_(q)SO₂NHaralkyl,—(CH₂)_(q)SO₂NHcycloalkyl, heterocyclenyl, heterocyclyl, and hetroaryl;

m is 0 to 4;

n is 0 to 4;

each q can be the same or different, each being independently selectedfrom 1 to 5; and

r is 1 to 4;

with the proviso that there are no two adjacent double bonds in anyring, and that when a nitrogen is substituted by two alkyl groups, saidtwo alkyl groups may be optionally joined to each other to form a ring.

A further feature of the invention is a pharmaceutical compositioncontaining as active ingredient at least one compound of Formula 1together with at least one pharmaceutically acceptable carrier orexcipient.

The invention provides methods of preparing compounds of Formula 1, aswell as methods for treating diseases, for example, treatment (e.g.,palliative therapy, curative therapy, prophylactic therapy) of certaindiseases and conditions e.g., inflammatory diseases (e.g., psoriasis,inflammatory bowel disease), autoimmune diseases (e.g., rheumatoidarthritis, multiple sclerosis), graft rejection (e.g., allograftrejection, xenograft rejection), ophthalmic inflammation or dry eye,infectious diseases and tumors. The invention provides a method oftreating a CXCR3 chemokine mediated disease in a patient in need of suchtreatment comprising administering to the patient a therapeuticallyeffective amount of at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof.

The invention provides methods of treating diseases, for example,treatment (e.g., palliative therapy, curative therapy, prophylactictherapy) of certain diseases and conditions such as inflammatorydiseases (e.g., psoriasis, inflammatory bowel disease), autoimmunediseases (e.g., rheumatoid arthritis, multiple sclerosis), graftrejection (e.g., allograft rejection, xenograft rejection), infectiousdiseases as well as cancers and tumors, fixed drug eruptions, cutaneousdelayed-type hypersensitivity responses, ophthalmic inflammation or dryeye, type I diabetes, viral meningitis and tuberculoid leprosycomprising administering: (a) a therapeutically effective amount of atleast one compound according to Formula 1, or a pharmaceuticallyacceptable salt, solvate or ester thereof concurrently or sequentiallywith (b) at least one medicament selected from the group consisting of:disease modifying antirheumatic drugs; nonsteroidal anti-inflammatorydrugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives(such as cyclosporins and methotrexate); steroids (includingcorticosteroids such as glucorticoids); PDE IV inhibitors, anti-TNF-αcompounds, TNF-α-convertase (TACE) inhibitors, MMP inhibitors, cytokineinhibitors, glucocorticoids, other chemokine inhibitors such as CCR2 andCCR5, CB2-selective inhibitors, p38 inhibitors, biological responsemodifiers; anti-inflammatory agents and therapeutics.

The invention also provides a method of modulating (inhibiting orpromoting) an inflammatory response in an individual in need of suchtherapy. The method comprises administering a therapeutically effectiveamount of a compound (e.g., small organic molecule) which inhibits orpromotes mammalian CXCR3 function in an individual in need thereof. Alsodisclosed is a method of inhibiting or blocking T-cell mediatedchemotaxis in a patient in need of such treatment comprisingadministering to the patient a therapeutically effective amount of acompound of Formula 1 or a pharmaceutically acceptable salt, solvate orester thereof.

Also disclosed is a method of treating inflammatory bowel disease (suchCrohn's disease, ulcerative colitis) in a patient in need of suchtreatment comprising administering to the patient a therapeuticallyeffective amount of at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof.

Also disclosed is a method of treating inflammatory bowel disease in apatient in need of such treatment comprising administering to thepatient a therapeutically effective amount of: (a) at least one compoundof Formula 1, or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one compoundselected from the group consisting of: sulfasalazine, 5-aminosalicylicacid, sulfapyridine, anti-TNF compounds, anti-IL-12 compounds,corticosteroids, glucocorticoids, T-cell receptor directed therapies(such as anti-CD3 antibodies), immunosuppresives, methotrexate,azathioprine, and 6-mercaptopurines.

Also disclosed is a method of treating graft rejection in a patient inneed of such treatment comprising administering to the patient atherapeutically effective amount of at least one compound of Formula 1,or a pharmaceutically acceptable salt, solvate or ester thereof.

Also disclosed is a method of treating graft rejection in a patient inneed of such treatment comprising administering to the patient atherapeutically effective amount of: (a) at least one compound ofFormula 1, or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one compoundselected from the group consisting of: cyclosporine A, FK-506, FTY720,beta-interferon, rapamycin, mycophenolate, prednisolone, azathioprine,cyclophosphamide and an antilymphocyte globulin.

Also disclosed is a method of treating multiple sclerosis in a patientin need of such treatment the method comprising administering to thepatient a therapeutically effective amount of: (a) a therapeuticallyeffective amount of at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one compound selected from the groupconsisting of: beta-interferon, glatiramer acetate, corticosteroids,glucocorticoids, methotrexate, azothioprine, mitoxantrone, VLA4inhibitors, FTY720, anti-IL-12 inhibitors, and CB2-selective inhibitors.

Also disclosed is a method of treating multiple sclerosis in a patientin need of such treatment the method comprising administering to thepatient a therapeutically effective amount of: (a) a therapeuticallyeffective amount of at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one compound selected from the groupconsisting of: methotrexate, cyclosporin, leflunomide, sulfasalazine,corticosteroids, β-methasone, β-interferon, glatiramer acetate,prednisone, etonercept, and infliximab.

Also disclosed is a method of treating rheumatoid arthritis in a patientin need of such treatment the method comprising administering to thepatient a therapeutically effective amount of: (a) at least one compoundof Formula 1, or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one compoundselected from the group consisting of: non-steroidal anti-inflammatoryagents, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives,cyclosporine, methotrexate, steroids, PDE IV inhibitors, anti-TNF-αcompounds, MMP inhibitors, corticosteroids, glucocorticoids, chemokineinhibitors, CB2-selective inhibitors, caspase (ICE) inhibitors and otherclasses of compounds indicated for the treatment of rheumatoidarthritis.

Also disclosed is a method of treating psoriasis in a patient in need ofsuch treatment the method comprising administering to the patient atherapeutically effective amount of: a) at least one compound of Formula1, or a pharmaceutically acceptable salt, solvate or ester thereofconcurrently or sequentially with (b) at least one compound selectedfrom the group consisting of: immunosuppressives, cyclosporins,methotrexate, steroids, corticosteroids, anti-TNF-α compounds, anti-ILcompounds, anti-IL-23 compounds, vitamin A and D compounds andfumarates.

Also disclosed is a method of treating ophthalmic inflammation(including, for e.g., uveitis, posterior segment intraocularinflammation, Sjogren's syndrome) or dry eye in a patient in need ofsuch treatment the method comprising administering to the patient atherapeutically effective amount of: a) at least one compound accordingto Formula 1, or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one compoundselected from the group consisting of: immunosuppressives, cyclosporins,methotrexate, FK506, steroids, corticosteroids, and anti-TNF-αcompounds.

Also disclosed is a method of treating a disease selected from the groupconsisting of: inflammatory disease, rheumatoid arthritis, multiplesclerosis, inflammatory bowel disease, graft rejection, psoriasis, fixeddrug eruptions, cutaneous delayed-type hypersensitivity responses,ophthalmic inflammation (including e.g., uveitis, posterior segmentintraocular inflammation, and Sjogren's syndrome), tuberculoid leprosyand cancer in a patient in need of such treatment, such methodcomprising administering to the patient an effective amount of at leastone compound according to Formula 1, or a pharmaceutically acceptablesalt, solvate or ester thereof.

The invention also provides a method of treating a disease selected fromthe group consisting of: inflammatory disease, rheumatoid arthritis,multiple sclerosis, inflammatory bowel disease, graft rejection,psoriasis, fixed drug eruptions, cutaneous delayed-type hypersensitivityresponses and tuberculoid leprosy, ophthalmic inflammation, type Idiabetes, viral meningitis and cancer in a patient in need of suchtreatment, such method comprising administering to the patient aneffective amount of (a) at least one compound according to Formula 1, ora pharmaceutically acceptable salt, solvate or ester thereofconcurrently or sequentially with (b) at least one medicament selectedfrom the group consisting of: disease modifying antirheumatic drugs;nonsteroidal antiinflammatory drugs; COX-2 selective inhibitors; COX-1inhibitors; immunosuppressives; steroids; PDE IV inhibitors, anti-TNF-αcompounds, MMP inhibitors, corticosteroids, glucocorticoids, chemokineinhibitors, CB2-selective inhibitors, biological response modifiers;anti-inflammatory agents and therapeutics.

DETAILED DESCRIPTION OF THE INVENTION

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence, the definition of “alkyl” applies to“alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,”“alkoxy,” etc.

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. The alkenyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxyl, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano,heteroaryl, heterocyclyl, heterocyclenyl, amino, aminosulfonyl, halo,carboxyl, carboxyalkyl (non-limiting example(s) include ester),alkoxycarbonyl, hydroxyalkyl, carbonyl (non-limiting example(s) includeketone), —C(═O)heterocyclyl, formyl (non-limiting example(s) includealdehyde), carboxamido (i.e. amido, —C(═O)NH₂), —C(═O)N(alkyl)₂,—C(═O)NH(alkyl), —C(═O)N(cycloalkyl)₂, —C(═O)NH(cycloalkyl),—NHC(═O)alkyl, urea (e.g. —NH(C═O)NH₂, —NH(C═O)NH(alkyl),—NH(C═O)NH(alkyl)₂, —NH(C═O)NH(heteroaryl), —NH(C═O)NH(heterocyclyl)),guanidinyl, —NHC(═NCN)NH₂, —NHC(═NCN)N(alkyl)₂, carbamoyl (i.e.—CO₂NH₂), NHC(═O)Oalkyl, —CO₂N(alkyl)₂, —NHC(═O))NH—S(O)₂alkyl,—NHC(═O)N(alkyl)₂—S(O)₂alkyl, —NH—S(O)₂alkyl, —NH—S(O)₂heteroaryl,—N(alkyl)-S(O)₂alkyl, —NH—S(O)₂aryl, —N(alkyl)-S(O)₂aryl, —NH—S(O)₂NH₂,—NH—S(O)₂NHalkyl, —NH—S(O)₂N(alkyl)₂, alkylthiocarboxy, —S(O)₂alkyl,—S(O)₂aryl, —OS(O)₂alkyl, —OS(O)₂aryl, sulfonyl urea (non-limitingexample(s) include NHC(═S)NHalkyl). Non-limiting examples of suitablealkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl,n-pentenyl, octenyl and decenyl.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The alkyl group may besubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxyl, aryl, aryloxy,cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl,heterocyclenyl,

amino, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —N(cycloalkyl)₂,—NH(aryl), —N(aryl)₂, —NH(heteroaryl), —N(heteroaryl)₂,—NH(heterocyclyl), N(heterocyclyl)₂, halo, hydroxy, carboxyl,carboxyalkyl (non-limiting example(s) include ester), alkoxycarbonyl,hydroxyalkyl, carbonyl (non-limiting example(s) include ketone),—C(═O)heterocyclyl, formyl, carboxamido (i.e. amido, —C(═O)NH₂,—C(═O)N(alkyl)₂, —C(═O)NH(alkyl), —C(═O)N(cycloalkyl)₂,—C(═O)NH(cycloalkyl)), —NHC(═O)alkyl, amidinyl, hydrazidyl, hydroxamate,—NHC(═O)H, —NHC(═O)alkyl, urea (non-limiting example(s) include—NH(C═O)NH₂, —NH(C═O)NH(alkyl), —NH(C═O)N(alkyl)₂,—NH(C═O)NH(heteroaryl), —NH(C═O)NH(heterocyclyl)), guanidinyl,—NHC(═NCN)NH₂, —NHC(═NCN)N(alkyl)₂, carbamoyl (i.e., —CO₂NH₂),—NHC(═O)Oalkyl, —CO₂N(alkyl)₂, —NHC(═O)NH—S(O)₂alkyl,—NHC(═O)N(alkyl)-S(O)₂alkyl, —NH—S(O)₂alkyl, —NH—S(O)₂heteroaryl,—N(alkyl)-S(O)₂alkyl, —NH—S(O)₂aryl, —N(alkyl)-S(O)₂aryl, —NH—S(O)₂NH₂,—NH—S(O)₂NHalkyl, —NH—S(O)₂N(alkyl)₂, thio, alkylthio, alkylthiocarboxy,—S(O)alkyl, —S(O)₂alkyl, —S(O)₂aryl, —OS(O)₂alkyl, —OS(O)₂aryl, sulfonylurea (non-limiting example(s) include —NHC(═S)NHalkyl) and OSi(alkyl)₃.Non-limiting examples of suitable alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl,fluoromethyl, trifluoromethyl and cyclopropylmethyl.

“Alkylheteroaryl” means an alkyl-heteroaryl-group wherein the alkyl isas previously described and the bond to the parent moiety is through theheteroaryl group.

“Alkylamino” means an —NH2 or —NH3+ group in which one or more of thehydrogen atoms on the nitrogen is replaced by an alkyl group as definedabove. The bond to the parent is through the nitrogen.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are asdescribed herein. Preferred alkylaryls comprise a lower alkyl group.Non-limiting examples of suitable alkylaryl groups include o-tolyl,p-tolyl and xylyl. The bond to the parent moiety is through the aryl.

“Alkylthio” means an alkyl-S— group in which the alkyl group is asdescribed herein. Non-limiting examples of suitable alkylthio groupsinclude methylthio, ethylthio, i-propylthio and heptylthio. The bond tothe parent moiety is through the sulfur.

“Alkylthiocarboxy” means an alkyl-S—C(═O)O— group. Preferred groups arethose in which the alkyl group is lower alkyl. The bond to the parentmoiety is through the carboxy.

“Alkylsulfonyl” means an alkyl-S(O)₂— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Alkylsulfinyl” means an alkyl-S(O)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfinyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.The alkynyl group may be substituted by one or more substituents whichmay be the same or different, each substituent being independentlyselected from the group consisting of alkyl, alkoxyl, aryl, aryloxy,cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl,heterocyclenyl, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl),—N(cycloalkyl)₂, —NH(aryl), —N(aryl)₂, —NH(heteroaryl), —N(heteroaryl)₂,—NH(heterocyclyl), N(heterocyclyl)₂, alkoxycarbonyl, hydroxyalkyl,carbonyl (non-limiting example(s) include ketone), —C(═O)heterocyclyl,carboxamido (i.e. amido, —C(═O)NH₂), —C(═O)N(alkyl)₂, —C(═O)NH(alkyl),—C(═O)N(cycloalkyl)₂, —C(═O)NH(cycloalkyl)), alkylC(═O)NH—,—NHC(═O)alkyl), urea (e.g. —NH(C═O)NH₂), —NH(C═O)NH(alkyl),—NH(C═O)NH(alkyl)₂, —NH(C═O)NH(heteroaryl), —NH(C═O)NH(heterocyclyl),—S(O)₂alkyl, and —S(O)₂aryl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy andmethylhydroxy. The bond to the parent moiety is through the etheroxygen.

“Alkoxycarbonyl” means an alkyl-O—C(═O)— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aminoalkyl” means an amine-alkyl-group in which alkyl is as previouslydefined. Preferred aminoalkyls contain lower alkyl. Non-limitingexamples of suitable aminoalkyl groups include aminomethyl and2-Dimethlylamino-2-ethyl. The bond to the parent moiety is through thealkyl.

“Amidinyl” means —C(═NR)NHR group. The R groups are defined as H, alkyl,alkylaryl, heteroaryl, hydroxyl, alkoxy, amino, ester, CN, —NHSO₂alkyl,—NHSO₂Aryl, —NHC(═O)NHalkyl, and —NHalkyl. The bond to the parent moietyis through the carbon.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group attached to the aryl group. Non-limiting examples ofsuitable aralkyl groups include phenymethylene, 2-phenethyl andnaphthalenylmethyl. The bond to the parent moiety is through the alkyl.

“Aralkenyl” means an aryl-alkenyl-group in which the aryl and alkenylare as previously described. Preferred aralkenyls contain a loweralkenyl group. Non-limiting examples of suitable aralkenyl groupsinclude 2-phenethenyl and 2-naphthylethenyl. The bond to the parentmoiety is through the alkenyl.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Aralkoxy” means an aralkyl-O— group in which the aralkyl group is asdescribed above. The bond to the parent moiety is through the oxygengroup.

“Aralkoxycarbonyl” means an aralkyl-O—C(═O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Aroyl” means an aryl-C(═O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1- and 2-naphthoyl.

“Aryl” (sometimes abbreviated “Ar”) means an aromatic monocyclic ormulticyclic ring system comprising about 6 to about 14 carbon atoms,preferably about 6 to about 10 carbon atoms. The aryl group can beoptionally substituted with one or more “ring system substituents” whichmay be the same or different, and are as defined herein. Non-limitingexamples of suitable aryl groups include phenyl and naphthyl.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aryloxycarbonyl” means an aryl-O—C(═O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Arylsulfonyl” means an aryl-S(O)₂— group. The bond to the parent moietyis through the sulfonyl.

“Arylsulfinyl” means an aryl-S(O)— group. The bond to the parent moietyis through the sulfinyl.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Carboxyalkyl” means an alkyl-C(═O)O— group. The bond to the parentmoiety is through the carboxy.

“Carboxamido” means —C(═O)NRR wherein R is H, alkyl, amino, aryl,cycloalkyl, heterocyclenyl, heteroaryl and carboxamido. The bond to theparent moiety is through the carboxy.

Carbamates and urea substituents refer to groups with oxygens andnitrogens respectively adjacent an amide; representative carbamate andurea substituents include the following:

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples can include bicyclic cycloalkylssuch as bicycloheptane. Non-limiting examples of suitable multicycliccycloalkyls include 1-decalin, norbornyl, adamantyl and the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl. The term “cycloalkenyl” additionally means moieties suchas cyclobutenedione, cyclopentenone, cyclopentenedione and the like.

“Halogen” (or halo) means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. The nitrogen or sulfur atom ofthe heteroaryl can be optionally oxidized to the corresponding N-oxide,S-oxide or S,S-dioxide. Non-limiting examples of suitable heteroarylsinclude pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl,isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl,pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl,phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocyclyl can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The nitrogen or sulfur atom of the heterocyclyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,oxazolidinyl, imidazolidinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-d ioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydroth iopyranyl, and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclicazaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine,1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetra hydropyrimidine, dihydro-2-pyrrolinyl,dihydro-3-pyrrolinyl, dihydro-2-imidazolinyl, dihydro-2-pyrazolinyl,dihydro-4,5-trizolyl and the like. Non-limiting examples of suitableoxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl,fluorodihydrofuranyl, and the like. Non-limiting example of a suitablemulticyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.Non-limiting examples of suitable monocyclic thiaheterocyclenyl ringsinclude thiophenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-(3-yl)methyl.The bond to the parent moiety is through the alkyl.

“Heteroaralkenyl” means an heteroaryl-alkenyl-group in which theheteroaryl and alkenyl are as previously described. Preferredheteroaralkenyls contain a lower alkenyl group. Non-limiting examples ofsuitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through thealkenyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl. The bond to the parent moiety is through the alkyl.

“Hydroxamate” means an alkyl-C(═O)NH—O— group. The bond to the parentmoiety is through the oxygen group.

“Spiroalkyl” means an alkylene group wherein two carbon atoms of analkyl group are attached to one carbon atom of a parent molecular groupthereby forming a carbocyclic or heterocyclic ring of three to elevenatoms. Representative structures include examples such as:

The spiroalkyl groups of this invention:

can be optionally substituted by one or more ring system substituents,wherein “ring system substituent” is as defined herein.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, alkoxyl, aryl, aroyl, aryloxy,cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, heterocyclenyl,alkylaryl, alkylheteroaryl, aralkyl, aralkenyl, aralkoxy,aralkoxycarbonyl, amino, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl),—N(cycloalkyl)₂, —NH(aryl), —N(aryl)₂, —NH(heteroaryl), —N(heteroaryl)₂,—NH(heterocyclyl), N(heterocyclyl)₂, halo, hydroxy, carboxyl,carboxyalkyl (non-limiting example(s) include ester), cyano,alkoxycarbonyl, hydroxyalkyl, carbonyl (non-limiting example(s) includeketone), —C(═O)heterocyclyl, formyl (non-limiting example(s) includealdehyde), carboxamido (i.e. amido, —C(═O)NH₂), —C(═O)N(alkyl)₂,—C(═O)NH(alkyl), —C(═O)N(cycloalkyl)₂, —C(═O)NH(cycloalkyl),alkylC(═O)NH—, -amidino, hydrazido, hydroxamate, —NHC(═O)H,—NHC(═O)alkyl, urea (e.g. —NH(C═O)NH₂), —NH(C═O)NH(alkyl),—NH(C═O)NH(alkyl)₂, —NH(C═O)NH(heteroaryl), —NH(C═O)NH(heterocyclyl),guanidinyl, —NHC(═NCN)NH₂, —NHC(═NCN)N(alkyl)₂, carbamoyl (i.e.—CO₂NH₂), NHC(═O)Oalkyl, —CO₂N(alkyl)₂, —NHC(═O))NH—S(O)₂alkyl,—NHC(═O)N(alkyl)₂—S(O)₂alkyl, —NH—S(O)₂alkyl, —NH—S(O)₂heteroaryl,—N(alkyl)-S(O)₂alkyl, —NH—S(O)₂aryl, —N(alkyl)-S(O)₂aryl, —NH—S(O)₂NH₂,—NH—S(O)₂NHalkyl, —NH—S(O)₂N(alkyl)₂, thio, alkylthiocarboxy,—S(O)₂alkyl —S(O)₂aryl, —OS(O)₂alkyl, —OS(O)₂aryl, sulfonyl urea(non-limiting example(s) include —NHC(═S)NHalkyl) and OSi(alkyl)₃.

“Ring system substituent” also means a cyclic ring of 3 to 7 ring atomsof which may contain 1 or 2 heteroatoms, attached to an aryl,heteroaryl, heterocyclyl or heterocyclenyl ring by simultaneouslysubstituting two ring hydrogen atoms on said aryl, heteroaryl,heterocyclyl or heterocyclenyl ring. Non-limiting examples include:

and the like.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties, in available position orpositions.

With reference to the number of moieties (non-limiting example(s)include, substituents, groups or rings) in a compound, unless otherwisedefined, the phrases “one or more” and “at least one” mean that, therecan be as many moieties as chemically permitted, and the determinationof the maximum number of such moieties is well within the knowledge ofthose skilled in the art. Preferably, there are one to threesubstituents, or more preferably, one to two substituents, with at leastone in the para position.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The straight line

as a bond generally indicates a mixture of, or either of, the possibleisomers, non-limiting example(s) include, containing (R)- and(S)-stereochemistry. For example,

means containing both

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples, structural formulae, and any Tables hereinis assumed to have the hydrogen atom or atoms to satisfy the valences.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of Formula 1 or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

Metabolic conjugates, for example, glucoronides and sulfates which canunder reversible conversion to compounds of Formula 1 are contemplatedin this application.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective to antagonize CXCR3 and thus produce the desired therapeuticeffect in a suitable patient.

“Mammal” means humans and other mammalian animals.

“Patient” includes both human and animals.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

The compounds of Formula 1 form salts which are also within the scope ofthis invention. Reference to a compound of Formula 1 herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula 1 contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (non-limiting example(s) include, non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the Formula 1 may be formed, for example, byreacting a compound of Formula 1 with an amount of acid or base, such asan equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization. Acids(and bases) which are generally considered suitable for the formation ofpharmaceutically useful salts from basic (or acidic) pharmaceuticalcompounds are discussed, for example, by S. Berge et al, Journal ofPharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. ofPharmaceutics (1986) 33 201-217; Anderson et al, The Practice ofMedicinal Chemistry (1996), Academic Press, New York; in The Orange Book(Food & Drug Administration, Washington, D.C. on their website); and P.Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of PharmaceuticalSalts: Properties, Selection, and Use, (2002) Int'l. Union of Pure andApplied Chemistry, pp. 330-331. These disclosures are incorporatedherein by reference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides(non-limiting example(s) include methyl, ethyl, propyl, and butylchlorides, bromides and iodides), dialkyl sulfates (non-limitingexample(s) include dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (non-limiting example(s) include decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(non-limiting example(s) include benzyl and phenethyl bromides), andothers.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

Compounds of Formula 1, and salts, solvates and prodrugs thereof, mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

It should also be noted that throughout the specification and Claimsappended hereto any formula, compound, moiety or chemical illustrationwith unsatisfied valences is assumed to have the hydrogen atom tosatisfy the valences unless the context indicates a bond.

In one embodiment, the present invention discloses compounds of Formula1, having CXCR3 antagonist activity, or a pharmaceutically acceptablederivative thereof, where the various definitions are given above.

In another embodiment, G is fused to said ring marked a via at leastsaid one N atom of ring G.

In another embodiment, ring G is selected from the group consisting of:

wherein

is a single bond or double bond.

In another embodiment, R³ is selected from the group consisting of H,alkyl, haloalkyl, hydroxyalkyl, halogen, —N(R³⁰)₂, —OR³⁰ and —CF₃.

In another embodiment, R³ is selected from the group consisting of H,—CH₃, —CH₂CH₃, cyclopropyl, —F, —Cl, OCH₃, OCF₃ and CF₃.

In another embodiment, R⁴ is selected from the group consisting of H,alkyl, halogen, hydroxyalkyl, —CN, —N(R³⁰)₂, —OR³⁰, —N═CH-alkyl, and—NR³⁰C(═O)alkyl.

In another embodiment, R⁴ is selected from the group consisting of H,—NH₂, —CH₃, —CN and —F.

In another embodiment, R⁸ is selected from the group consisting of H,alkyl, alkenyl, arylalkyl, cycloalkyl, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹,—(CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹, —(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹,—(CH₂)_(q)NSO₂R³¹, and —(CH₂)_(q)SO₂NHR³¹.

In another embodiment, the R⁹ moieties can be the same or different,each being independently selected from the group consisting of H, alkyl,cycloalkyl, —C(═O)N(H)R³⁰, —C(═O)alkyl, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹,—(CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹, —N(H)R³⁰, —N(H)S(O₂)R³¹,—N(H)C(═O)NH(R³⁰), —OR³⁰—SO₂(R³¹), and —SO₂N(H)R³⁰.

In another embodiment, the R⁹ moieties can be the same or different,each being independently selected from the group consisting of H,cyclopropyl, —CF₃, —CH₃, —CH₂OH, —CH₂CH₂OH, —C(CH₃)₂OH, —CH₂CH₂OCH₃,—C(═O)OCH₂CH₃, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂NHSO₂CH₃, —CH₂CH₂SO₂CH₃,—C(═O)NH₂, —C(═O)N(H)CH₂CH₂OH, —CH₂N(H)C(═O)CF₃, —C(═O)N(H)-cyclopropyl,—C(═O)N(H)CH₂CF₃, —NH₂, —NHCH₃, —N(CH₃)₂, —N(H)CH₂CH₃, —N(H)CH(CH₃)₂,—N(H)CH₂CH₂CH₃, —N(H)CH₂C(═O)OCH₃, —N(H)CH₂CH₂OH, —N(H)CH₂CH₂NH₂,—N(H)CH₂CH₂NHSO₂CH₃, —N(H)CH₂CH₂SO₂CH₃, —N(H)C(═O)N(H)CH₂CH₃,—N(H)CH₂C(═O)NH₂, —OCH₃, ═S and ═O.

In another embodiment, the R⁹ moieties can be the same or different,each being independently selected from the group consisting of H, —CF₃,—CH₃, —CH₂CH₂OH, —CH₂CH₂NH₂, —NH₂, —NHCH₃, —N(H)CH₂CH₃, —N(H)CH(CH₃)₂,—N(H)CH₂CH₂CH₃, —N(H)CH₂C(═O)OCH₃, and —N(H)CH₂CH₂OH.

In another embodiment, R¹⁰ is selected from the group consisting of H,alkyl, aralkyl, hydroxyalkyl, and carbonyl.

In another embodiment, R¹⁰ is selected from the group consisting of—CH₃, —CH₂CH₃ and —CH₂CH₂CH₃, and m is 0-2.

In another embodiment, R¹¹ is selected from the group consisting of H,alkyl, hydroxyalkyl and carbonyl.

In another embodiment, R¹¹ is H or —CH₃.

In another embodiment, R¹² is selected from the group consisting of H,CN, —C(═O)N(R³⁰)₂ and alkyl.

In another embodiment, R¹² is selected from the group consisting of H,—CH₃, CN and —CH₂CH₃.

In another embodiment, the ring atoms of ring D are independently C or Nand substituted by 0-4 R²⁰ moieties.

In another embodiment, ring D is a 5 to 6 membered aryl, heteroaryl,heterocyclenyl, or heterocyclyl ring and substituted by 0-4 R²⁰moieties.

In another embodiment, the R²⁰ moieties can be the same or different,each being independently selected from the group consisting of H, alkyl,alkylaryl, alkynyl, alkoxy, alkylamino, alkylheteroaryl, alkylsulfinyl,alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkoxy, aryl, aryloxy,cyano, cycloalkyl, cycloalkenyl, halogen, haloalkyl, heteroalkyl,heteroaryl, heterocyclyl, hydroxyalkyl, trifluromethyl,trifluoromethoxy, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NHR³¹, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹,-alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)N(R³⁰)₂, —C(═O)OR³⁰, —N(R³⁰)₂,—N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹,—N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)₂, —N(R³⁰)SO₂(R³¹),—N(R³⁰)SO₂N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂, —SR³⁰, —SO₂N(R³⁰)₂, —SO₂(R³¹),—OSO₂(R³¹), and —OSi(R³⁰)₃.

In another embodiment, the R²⁰ moieties can be the same or different,each being independently selected from the group consisting of H, alkyl,amino, halogen, CN, CH₃, CF₃, OCF₃, —(CH₂)_(q)OR³, —(CH₂)_(q)NHR³¹,—(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹,—(CH₂)_(q)SO₂NHR³¹, -alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)OR³⁰,—N(R³⁰)₂, —N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹,—N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂, and—OSO₂(R³¹).

In another embodiment, two R²⁰ moieties are linked together to form afive or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl orheteroaryl ring wherein said five or six membered aryl, cycloalkyl,heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D andthe fused ring is optionally substituted with 0 to 4 R²¹ moieties.

In another embodiment, the R²⁰ moieties can be the same or different,each being independently selected from the group consisting of H, —CN,—CH₃, —CF₃, —CH₂OH, —CO₂H, —CO₂CH₃, —NH₂, —NHCH₃, —OCF₃, —OH, F, Cl, Br,—C(═NOH)NH₂, —OCH₂CH₂S(O₂)CH₃, —C(═O)NH₂,

In another embodiment, Y is selected from the group consisting of:—(CHR¹³)_(r)—, —(CR¹³R¹³)_(r)—, —C(═O)— and —CHR¹³C(═O)—.

In another embodiment, Y is selected from the group consisting of:—CH₂—, —CH(CH₃)—, —CH(CH₂OH)—, —C(═O)— and —CH(CO₂alkyl)-.

In another embodiment, m is 0-2.

In another embodiment, n is 0-2.

In another embodiment, q is 1 or 2.

In another embodiment, r is 1 or 2.

In another embodiment, ring G is selected from the group consisting of:

is a single bond or a double bond;

R³ is selected from the group consisting of H, alkyl, haloalkyl,hydroxyalkyl, halogen, —N(R³⁰)₂, —OR³⁰ and —CF₃;

R⁶ is selected from the group consisting of H, alkyl, halogen,hydroxyalkyl, —CN, —N(R³⁰)₂, —OR³⁰, —N═CH-alkyl, and —NR³⁰OC(═O)alkyl;

R⁹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, cycloalkyl,—C(═O)N(H)R³⁰, —C(═O)alkyl, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂,—(CH₂)_(q)NHR³¹, —N(H)R³⁰, —N(H)S(O₂)R³¹, —N(H)C(═O)NH(R³⁰), —OR³⁰,—SO₂(R³¹), and —SO₂N(H)R³⁰;

R¹⁰ is selected from the group consisting of H, alkyl, aralkyl,hydroxyalkyl, and carbonyl;

R¹¹ is selected from the group consisting of: H, alkyl, hydroxyalkyl,and carbonyl;

R¹² is selected from the group consisting of H, CN, —C(═O)N(R³⁰)₂ andalkyl;

ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, orheterocyclyl ring and substituted by 0-4 R²⁰ moieties;

the R²⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, amino, halogen, CN, CH₃,CF₃, OCF₃, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NHR³¹, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹,-alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)OR³⁰, —N(R³⁰)₂, —N(R³⁰)C(═O)R³¹,—NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹, —N(R³⁰)C(═NCN)N(R³⁰)₂,—N(R³⁰)C(═O)N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂,

and —OSO₂(R³¹)

Y is selected from the group consisting of: —CH₂—, —CH(CH₃)—,—CH(CH₂OH)—, —C(═O)— and —CH(CO₂alkyl)-;

m is 0-2;

n is 0-2;

q is 1 or 2; and

r is 1 or 2.

In another embodiment, the compound of Formula 1 is represented bystructural Formula 2, Formula 3, Formula 4 or Formula 5:

wherein:

the R⁸ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl,—(CH₂)_(q)OH, (CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹,—(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹, or—(CH₂)_(q)SO₂NHR³¹;

the R⁹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, arylalkyl, alkylaryl,cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, —C(═O)N(H)R³⁰,—C(═O)alkyl, —N(H)R³⁰, —N(H)S(O₂)R³¹, —N(H)C(═O)NH(R³⁰), —OR³⁰,—SO₂(R³¹), ═O, ═S, and —SO₂N(H)R³⁰;

L is C or N; and

m, n, q, R¹⁰, R¹¹, R¹², R²⁰ and Y are as defined in claim 1.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, R³ is selected from the group consisting of H, alkyl,haloalkyl, hydroxyalkyl, halogen, —N(R³⁰)₂, —OR³⁰ and —CF₃.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, R⁶ is selected from the group consisting of H, alkyl,halogen, —N(R³⁰)₂, —OR³⁰ and —NR¹C(═O)alkyl.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, R⁹ moieties are the same or different, each beingindependently selected from the group consisting of H, cyclopropyl,—CF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —C(CH₃)₂OH, —CH₂CH₂OCH₃,—C(═O)OCH₂CH₃, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂NHSO₂CH₃, —CH₂CH₂SO₂CH₃,—C(═O)NH₂, —C(═O)N(H)CH₂CH₂OH, —CH₂N(H)C(═O)CF₃, —C(═O)N(H)-cyclopropyl,—C(═O)N(H)CH₂CF₃, —NH₂, —NHCH₃, —N(CH₃)₂, —N(H)CH₂CH₃, —N(H)CH(CH₃)₂,—N(H)CH₂CH₂CH₃, —N(H)CH₂C(═O)OCH₃, —N(H)CH₂CH₂OH, —N(H)CH₂CH₂NH₂,—N(H)CH₂CH₂NHSO₂CH₃, —N(H)CH₂CH₂SO₂CH₃, —N(H)C(═O)N(H)CH₂CH₃,—N(H)CH₂C(═O)NH₂, ═O, ═S, and —OCH₃.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, R¹⁰ is selected from the group consisting of H, alkyl,aralkyl, hydroxyalkyl, and carbonyl.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, R¹¹ is selected from the group consisting of: H, alkyland carbonyl.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, R¹² is selected from the group consisting of H, —CH₃, CNor —CH₂CH₃.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, R²⁰ moieties can be the same or different, each beingindependently selected from the group consisting of H, alkyl, amino,halogen, CN, CH₃, CF₃, OCF₃, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NHR³¹,—(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹,—(CH₂)_(q)SO₂NHR³¹, -alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)OR³⁰,—N(R³⁰)₂, —N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹,—N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂,—OSO₂(R³¹),

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, the R²⁰ moieties can be the same or different, eachbeing independently selected from the group consisting of H, —CN, —CH₃,—CF₃, —CH₂OH, —CO₂H, —CO₂CH₃, —NH₂, —NHCH₃, —OCF₃, —OH, F, Cl, Br,—C(═NOH)NH₂, —OCH₂CH₂S(O₂)CH₃, —C(═O)NH₂,

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, L is carbon.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, L is nitrogen.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, Y is selected from the group consisting of: —CH₂—,—C(═O)—, —CH(CH₂OH)— and —CH(CO₂alkyl)-.

In another embodiment, in the above-shown Formula 2, Formula 3, Formula4 or Formula 5, R³ is selected from the group consisting of H, alkyl,haloalkyl, hydroxyalkyl, halogen, —N(R³⁰)₂, —OR³⁰ and —CF₃;

R⁶ is selected from the group consisting of H, alkyl, halogen, —N(R³⁰)₂,—OR³⁰, and —NR¹C(═O)alkyl;

the R⁹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, cycloalkyl,—C(═O)N(H)R³⁰, —C(═O)alkyl, —N(H)R³⁰, —N(H)S(O₂)R³¹, —N(H)C(═O)NH(R³⁰),—OR³⁰, —SO₂(R³¹), and —SO₂N(H)R³⁰;

R¹⁰ is selected from the group consisting of H, alkyl, aralkyl,hydroxyalkyl and carbonyl;

the R²⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, amino, halogen, CN, CH₃,CF₃, OCF₃, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NHR³¹, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹,-alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)OR³⁰, —N(R³⁰)₂, —N(R³⁰)C(═O)R³¹,—NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹, —N(R³⁰)C(═NCN)N(R³⁰)₂,—N(R³⁰)C(═O)N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂, and —OSO₂(R³¹),

Y is selected from the group consisting of: —CH₂—, —C(═O)—, —CH(CH₂OH)—and —CH(CO₂alkyl)-;

m is 0-2;

q is 1, 2 or 3; and

r is 1 or 2.

In still another embodiment of the present invention, a compound isselected from the following structures in Table 1 below (or apharmaceutically acceptable salt or solvate thereof) which are shownalong with their IC₅₀ ratings. The IC₅₀ values are rated, “A” for IC₅₀values less than about 25 nanomolar (nM), “B” for IC₅₀ values in therange of from about 25 to about 100 nM and “C” for IC₅₀ values greaterthan about 100 nM. For example, Compound Number 1 has a IC₅₀ value of0.3 nM.

TABLE 1 Compound Number STRUCTURE IC₅₀ 1

A 2

A 3

A 4

A 5

A 6

A 7

A 8

A 9

A 10

A 11

A 12

A 13

A 14

A 15

A 16

A 17

A 18

B 19

B 20

B 21

B 22

B 23

B 24

B 25

C 26

C 27

C 28

C 29

C 30

C 31

C 32

C 33

C 34

C 35

C 36

C 37

C 38

Cor a pharmaceutically acceptable salt, solvate or ester thereof.

For example, the compound according to Formula 1 can be selected fromthe group consisting of compounds of the formulae:

or a pharmaceutically acceptable salt, solvate or ester thereof. Thehuman IC₅₀ values (in nM) of the above compounds have been set forthabove underneath their chemical structures.

In yet another aspect, this invention discloses the following compounds:

or pharmaceutically acceptable salts, solvates or esters thereof. Thehuman IC₅₀ values (in nM) of the above compounds have been set forthabove underneath their chemical structures.

In yet another aspect, the compound according to Formula 1 is inpurified form.

In another embodiment, this invention provides a pharmaceuticalcomposition comprising at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof incombination with at least one pharmaceutically acceptable carrier.

In still another embodiment, the invention provides a pharmaceuticalcomposition of Formula 1, further comprising at least one additionalagent, drug, medicament, antibody and/or inhibitor for treating a CXCR3chemokine receptor mediated disease.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts). Thus, for non-limiting illustration purposes, acompound of Formula III and an additional therapeutic agent may bepresent in fixed amounts (dosage amounts) in a single dosage unit (e.g.,a capsule, a tablet and the like). A commercial example of such singledosage unit containing fixed amounts of two different active compoundsis VYTORIN® (available from Merck Schering-Plough Pharmaceuticals,Kenilworth, N.J.).

In yet another embodiment, the present invention discloses methods forpreparing pharmaceutical compositions comprising the inventiveheterocyclic substituted piperazine compounds of Formula 1 as an activeingredient. In the pharmaceutical compositions and methods of thepresent invention, the active ingredients will typically be administeredin admixture with suitable carrier materials suitably selected withrespect to the intended form of administration, i.e. oral tablets,capsules (either solid-filled, semi-solid filled or liquid filled),powders for constitution, oral gels, elixirs, dispersible granules,syrups, suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier, suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Moreover, when desired or needed, suitable binders,lubricants, disintegrating agents and coloring agents may also beincorporated in the mixture. Powders and tablets may be comprised offrom about 5 to about 95 percent inventive composition. Suitable bindersinclude starch, gelatin, natural sugars, corn sweeteners, natural andsynthetic gums such as acacia, sodium alginate, carboxymethylcellulose,polyethylene glycol and waxes. Among the lubricants there may bementioned for use in these dosage forms, boric acid, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrants includestarch, methylcellulose, guar gum and the like. Sweetening and flavoringagents and preservatives may also be included where appropriate. Some ofthe terms noted above, namely disintegrants, diluents, lubricants,binders and the like, are discussed in more detail below.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. anti-inflammatory activity andthe like. Suitable dosage forms for sustained release include layeredtablets containing layers of varying disintegration rates or controlledrelease polymeric matrices impregnated with the active components andshaped in tablet form or capsules containing such impregnated orencapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and pacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions may take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active components, e.g., aneffective amount to achieve the desired purpose.

The quantity of the inventive active composition in a unit dose ofpreparation may be generally varied or adjusted from about 1.0 milligramto about 1,000 milligrams, preferably from about 1.0 to about 950milligrams, more preferably from about 1.0 to about 500 milligrams, andtypically from about 1 to about 250 milligrams, according to theparticular application. The actual dosage employed may be varieddepending upon the patient's age, sex, weight and severity of thecondition being treated. Such techniques are well known to those skilledin the art.

Generally, the human oral dosage form containing the active ingredientscan be administered 1 or 2 times per day. The amount and frequency ofthe administration will be regulated according to the judgment of theattending clinician. A generally recommended daily dosage regimen fororal administration may range from about 1.0 milligram to about 1,000milligrams per day, in single or divided doses.

Some useful terms are described below:

Capsule—refers to a special container or enclosure made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch forholding or containing compositions comprising the active ingredients.Hard shell capsules are typically made of blends of relatively high gelstrength bone and pork skin gelatins. The capsule itself may containsmall amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet—refers to a compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction.

Oral gels—efers to the active ingredients dispersed or solubilized in ahydrophillic semi-solid matrix.

Powders for constitution—refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

Diluent—refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include sugars such aslactose, sucrose, mannitol and sorbitol; starches derived from wheat,corn, rice and potato; and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about10 to about 90% by weight of the total composition, preferably fromabout 25 to about 75%, more preferably from about 30 to about 60% byweight, even more preferably from about 12 to about 60%.

Disinteqrants—refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellu lose and sodium carboxymethylcellu lose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

Binders—refers to substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose; starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

Lubricant—refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as sodium chloride, sodium benzoate, sodiumacetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricantsare usually added at the very last step before compression, since theymust be present on the surfaces of the granules and in between them andthe parts of the tablet press. The amount of lubricant in thecomposition can range from about 0.2 to about 5% by weight of thecomposition, preferably from about 0.5 to about 2%, more preferably fromabout 0.3 to about 1.5% by weight.

Glidents—materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

Coloring agents—excipients that provide coloration to the composition orthe dosage form. Such excipients can include food grade dyes and foodgrade dyes adsorbed onto a suitable adsorbent such as clay or aluminumoxide. The amount of the coloring agent can vary from about 0.1 to about5% by weight of the composition, preferably from about 0.1 to about 1%.

Bioavailability—refers to the rate and extent to which the active drugingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control.

Conventional methods for preparing tablets are known. Such methodsinclude dry methods such as direct compression and compression ofgranulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

It will be apparent to those skilled in the art that many modifications,variations and alterations to the present disclosure, both to materialsand methods, may be practiced. Such modifications, variations andalterations are intended to be within the spirit and scope of thepresent invention.

As stated earlier, the invention includes tautomers, enantiomers andother stereoisomers of the compounds also. Thus, as one skilled in theart knows, certain imidazole compounds may exist in tautomeric forms.Such variations are contemplated to be within the scope of theinvention. Certain compounds of the present invention may exist inmultiple crystalline forms or amorphous forms. All physical forms of thecurrent invention are contemplated.

Compounds of this invention which contain unnatural proportions ofatomic isotopes (i.e. “radiolabeled compounds”) whether their use istherapeutic, diagnostic or as a research reagent are contemplated underthis invention.

Another embodiment of the invention discloses the use of thepharmaceutical compositions disclosed above for treatment of diseases ofa CXCR3 chemokine receptor mediated disease in a patient in need of suchtreatment comprising administering to the patient a therapeuticallyeffective amount of at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof.

In another embodiment, the method is directed to administering to thepatient (a) an effective amount of at least one compound according toFormula 1, or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one additionalagent, drug, medicament, antibody and/or inhibitor for treating a CXCR3chemokine receptor mediated disease, in combination with apharmaceutically acceptable carrier.

In another embodiment, at least one compound of Formula 1 binds to aCXCR3 receptor.

The method can further comprise administering: (a) a therapeuticallyeffective amount of at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one medicament selected from the groupconsisting of: disease modifying antirheumatic drugs; nonsteroidalanti-inflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors;immunosuppressives (such as cyclosporins and methotrexate); steroids(including corticosteroids such as glucorticoids); PDE IV inhibitors,anti-TNF-α compounds, TNF-α-convertase (TACE) inhibitors, MMPinhibitors, cytokine inhibitors, glucocorticoids, other chemokineinhibitors such as CCR2 and CCR5, CB2-selective inhibitors, p38inhibitors, biological response modifiers; anti-inflammatory agents andtherapeutics. The disease can be an inflammatory disease (e.g.,psoriasis, inflammatory bowel disease)

Another embodiment of this invention is directed to a method ofinhibiting or blocking T-cell mediated chemotaxis in a patient in needof such treatment the method comprising administering to the patient atherapeutically effective amount of at least one compound according toFormula 1 or a pharmaceutically acceptable salt, solvate or esterthereof.

Another embodiment of this invention is directed to a method of treatinginflammatory bowel disease (such Crohn's disease, ulcerative colitis) ina patient in need of such treatment comprising administering to thepatient a therapeutically effective amount of at least one compoundaccording to Formula 1, or a pharmaceutically acceptable salt, solvateor ester thereof.

Another embodiment of this invention is directed to a method of treatinginflammatory bowel disease in a patient in need of such treatmentcomprising administering to the patient a therapeutically effectiveamount of:

(a) at least one compound of Formula 1, or a pharmaceutically acceptablesalt, solvate or ester thereof concurrently or sequentially with (b) atleast one compound selected from the group consisting of: sulfasalazine,5-aminosalicylic acid, sulfapyridine, anti-TNF compounds, anti-IL-12compounds, corticosteroids, glucocorticoids, T-cell receptor directedtherapies (such as anti-CD3 antibodies), immunosuppresives,methotrexate, azathioprine, and 6-mercaptopurines.

Another embodiment of this invention is directed to a method of treatingor preventing graft rejection in a patient in need of such treatmentcomprising administering to the patient a therapeutically effectiveamount of at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of this invention is directed to a method comprisingadministering to the patient a therapeutically effective amount of: (a)at least one compound according to Formula 1, or a pharmaceuticallyacceptable salt, solvate or ester thereof concurrently or sequentiallywith (b) at least one compound selected from the group consisting of:cyclosporine A, FK-506, FTY720, beta-interferon, rapamycin,mycophenolate, prednisolone, azathioprine, cyclophosphamide and anantilymphocyte globulin.

Another embodiment of this invention is directed to a method of treatingmultiple sclerosis in a patient in need of such treatment the methodcomprising administering to the patient a therapeutically effectiveamount of: (a) at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one compound selected from the groupconsisting of: beta-interferon, glatiramer acetate, corticosteroids,glucocorticoids, methotrexate, azothioprine, mitoxantrone, VLA-4inhibitors, FTY720, anti-IL-12 inhibitors, and CB2-selective inhibitors.

Another embodiment of this invention is directed to a method of treatingmultiple sclerosis in a patient in need of such treatment the methodcomprising administering to the patient a therapeutically effectiveamount of: a) at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one compound selected from the groupconsisting of: methotrexate, cyclosporin, leflunomide, sulfasalazine,corticosteroids, β-methasone, β-interferon, glatiramer acetate,prednisone, etonercept, and infliximab.

Another embodiment of this invention is directed to a method of treatingrheumatoid arthritis in a patient in need of such treatment the methodcomprising administering to the patient a therapeutically effectiveamount of: (a) at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one compound selected from the groupconsisting of: non-steroidal anti-inflammatory agents, COX-2 inhibitors,COX-1 inhibitors, immunosuppressives, cyclosporine, methotrexate,steroids, PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors,corticosteroids, glucocorticoids, chemokine inhibitors, CB2-selectiveinhibitors, caspase (ICE) inhibitors and other classes of compoundsindicated for the treatment of rheumatoid arthritis.

Another embodiment of this invention is directed to a method of treatingpsoriasis in a patient in need of such treatment the method comprisingadministering to the patient a therapeutically effective amount of: a)at least one compound according to Formula 1, or a pharmaceuticallyacceptable salt, solvate or ester thereof concurrently or sequentiallywith (b) at least one compound selected from the group consisting of:immunosuppressives, cyclosporins, methotrexate, steroids,corticosteroids, anti-TNF-α compounds, anti-IL compounds, anti-IL-23compounds, vitamin A and D compounds and fumarates.

Another embodiment of this invention is directed to a method of treatingophthalmic inflammation (including, for e.g., uveitis, posterior segmentintraocular inflammation, Sjogren's syndrome) or dry eye in a patient inneed of such treatment the method comprising administering to thepatient a therapeutically effective amount of: a) at least one compoundaccording to Formula 1, or a pharmaceutically acceptable salt, solvateor ester thereof concurrently or sequentially with (b) at least onecompound selected from the group consisting of: immunosuppressives,cyclosporins, methotrexate, FK506, steroids, corticosteroids, andanti-TNF-α compounds.

Another embodiment of this invention is directed to a method of treatinga disease selected from the group consisting of: inflammatory disease,rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease,graft rejection, psoriasis, fixed drug eruptions, cutaneous delayed-typehypersensitivity responses, ophthalmic inflammation (including e.g.,uveitis, posterior segment intraocular inflammation, and Sjogren'ssyndrome), tuberculoid leprosy and cancer in a patient in need of suchtreatment, such method comprising administering to the patient aneffective amount of at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of this invention is directed to a method of treatinga disease selected from the group consisting of inflammatory disease,rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease,graft rejection, psoriasis, fixed drug eruptions, cutaneous delayed-typehypersensitivity responses and tuberculoid leprosy, ophthalmicinflammation, type I diabetes, viral meningitis and cancer in a patientin need of such treatment, such method comprising administering to thepatient an effective amount of (a) at least one compound according toFormula 1, or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one medicamentselected from the group consisting of: disease modifying antirheumaticdrugs; nonsteroidal antiinflammatory drugs; COX-2 selective inhibitors;COX-1 inhibitors; immunosuppressives; steroids; PDE IV inhibitors,anti-TNF-α compounds, MMP inhibitors, corticosteroids, glucocorticoids,chemokine inhibitors, CB2-selective inhibitors, biological responsemodifiers; anti-inflammatory agents and therapeutics.

Another embodiment of the invention discloses a method of making theinventive compounds disclosed above.

Unless otherwise stated, the following abbreviations have the statedmeanings in the Examples below:

-   -   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene    -   DBN=1,5-diazabicyclo[4.3.0]non-5-ene    -   EDCl=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    -   HOBT=1-hydroxybenzotriazole    -   HATU=O-(7-Azabenzotriazol-1-yl)-N,N, N′,N′-tetramethyluronium        hexafluorophosphate    -   DCC=dicyclohexylcarbodiimide    -   Dibal-H=diisobutylaluminum hydride    -   LAH=lithium aluminum hydride    -   NaBH(OAc)₃=sodium triacetoxyborohydride    -   NaBH₄=sodium borohydride    -   NaBH₃CN=sodium cyanoborohydride    -   LDA=lithium diisopropylamide    -   p-TsOH=p-toluenesulfonic acid    -   m-CPBA=m-Chloroperbenzoic acid    -   TMAD=N,N,N′,N′-tetramethylazod icarboxamide    -   CSA=camphorsulfonic acid    -   NaHMDS=sodium hexamethyl disilylazide    -   HRMS=High Resolution Mass Spectrometry    -   HPLC=High Performance Liquid Chromatography    -   LRMS=Low Resolution Mass Spectrometry    -   nM=nanomolar    -   Ki=Dissociation Constant for substrate/receptor complex    -   pA2=−log EC₅₀, as defined by J. Hey, Eur. J. Pharmacol., (1995),        Vol. 294, 329-335.    -   Ci/mmol=Curie/mmol (a measure of specific activity)    -   Tr=Triphenylmethyl    -   Tris=Tris (hydroxymethyl)aminomethane

General Synthesis

Compounds of the present invention can be prepared by a number of waysevident to one skilled in the art. Preferred methods include, but arenot limited to, the general synthetic procedures described herein. Oneskilled in the art will recognize that one route will be optimaldepending on the choice of appendage substituents. Additionally, oneskilled in the art will recognize that in some cases the order of stepshas to be controlled to avoid functional group incompatibilities. Oneskilled in the art will recognize that a more convergent route (i.e.non-linear or preassembly of certain portions of the molecule) is a moreefficient method of assembly of the target compounds. Methods for thepreparation of compounds of general Formula 1 where variables [R¹, R³,R¹⁰, R¹¹, R¹², R²⁰, T, X, Q, V, Z, Q, L Y, k, m, n, o, w and p] asdefined above, are shown in schemes 1 through scheme 5. Pr¹, Pr² and Pr³are protecting groups exemplified below.

The prepared compounds may be analyzed for their composition and purityas well as characterized by standard analytical techniques such as, forexample, elemental analysis, NMR, mass spectroscopy, and IRspectroscopy.

The starting material and reagents used in preparing compounds describedare either available from commercial suppliers such as Aldrich ChemicalCo. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA) or wereprepared by literature methods known to those skilled in the art.

The preparation of arylpiperazine compounds related to intermediate IIIhas been reported in WO-03037862 (Nippon Shinyaku).

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the need for the protection of certain functionalgroups (i.e. derivatization for the purpose of chemical compatibilitywith a particular reaction condition). A suitable protecting group for acarboxylic acid (Pr¹, when R29 and R⁸ taken together is ═O) is methyl,ethyl, isopropyl, or benzyl ester and the like. A suitable protectinggroup for an amine (Pr², Pr³) is methyl, benzyl, ethoxycarbonyl,t-butoxycarbonyl, phthaloyl, trifluoroacetyl, acetyl and the like. Allprotecting groups can be appended to and removed by literature methodsknown to those skilled in the art.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the construction of an amide bond. Methods includebut are not limited to the use of a reactive carboxyl derivative (e.g.acid halide, or ester at elevated temperatures) or the use of an acidwith coupling reagents (e.g. EDCl, DCC, HATU) in the presence of anamine at 0° C. to 100° C. Suitable solvents for the reaction arehalogenated hydrocarbons, ethereal solvents, N,N-dimethylformamide andthe like. The reaction may be conducted under pressure or in a sealedvessel.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the construction of an amine bond. One such methodis, but not limited to, the reaction of a primary or secondary aminewith a reactive carbonyl (e.g. aldehyde or ketone) under reductiveamination conditions. Suitable reducing agents of the intermediate imineare sodium borohydride, sodium triacetoxyborohydride and the like at 0°C. to 100° C. Suitable solvents for the reaction are halogenatedhydrocarbons, ethereal solvents, N,N-dimethylformamide and the like.Another such method is but not limited to the reaction of a primary orsecondary amine with a reactive alkylating agent such as an alkylhalide, benzyl halide, mesylate, tosylate and the like. Suitablesolvents for the reaction are halogenated hydrocarbons, etherealsolvents, N,N-dimethylformamide and the like. The reaction may beconducted under pressure or in a sealed vessel at 0° C. to 100° C.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the reduction of a reducible functional group.Suitable reducing agents include sodium borohydride, lithium aluminumhydride, diborane and the like at −20° C. to 100° C. Suitable solventsfor the reaction are halogenated hydrocarbons, ethereal solvents,N,N-dimethylformamide and the like.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the oxidation of a functional group. Suitableoxidizing reagents include oxygen, hydrogen peroxide,m-chloroperoxybenzoic acid and the like at −20° C. to 100° C. Suitablesolvents for the reaction are halogenated hydrocarbons, etherealsolvents, water and the like.

One skilled in the art will note that compounds of Formula 1 require theconstruction of a heterocyclic ring. Numerous reviews of methodology forthe construction of specific heterocyclic systems are in the openliterature. In addition to the open literature, monographs andcompendiums such as “Comprehensive Heterocyclic Synthesis” (PergamonPress) are available. Shown below is only one such general methodologyfor the title compounds.

The starting materials and the intermediates of a reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials can be characterized usingconventional means, including physical constants and spectral data.

General Description of Methods

Step A. Amination of Pyrazine Ring

A suitably protected 2-halopyrazine of structure I or structure XVII isreacted with a piperazine of structure II to form a compound ofstructure III or structure XVIII. Preferably the reaction is carried outin a solvent such as dioxane in the presence of a base such as potassiumcarbonate or cesium carbonate. Optionally, a catalyst such as palladiumacetate may be added and the reaction heated to a temperature between30° C. to 150° C.

Alternatively, other leaving groups may replace the chlorine (O-mesyl,Br etc.) or a group capable of activation under the reaction conditions(H, OH, etc.) may be used.

Step B. Deprotection of Amine Protecting Group

Optionally, if the product of step A is a protected piperazine ofstructure III or structure XVIII, deprotection is required. When Pr² isbenzyl or substituted benzyl deprotection can be effected by reactionunder a pressure of hydrogen gas in the presence of a catalyst such aspalladium. When Pr² is ethoxycarbonyl deprotection can be effected byreaction with trimethylsilyl iodide. When Pr² is t-butoxycarbonyldeprotection can be effected with a strong acid such as trifluoroaceticacid.

Step C. Reductive Amination

A piperazine of structure IV or XIX is reacted with a compound ofstructure V or IX in the presence of a reducing agent with or withouttitanium tetraisopropoxide to form a compound of structure VI, X or XXwhere R¹² is hydrogen.

One variation to afford compounds of structure V or 1× with R¹²═CN, isthe reaction in the presence of a reducing agent with or withouttitanium tetraisopropoxide and a cyanide source such as dimethylaluminumcyanide.

General conditions for the reductive amination reaction are describedabove.

Step D. Hydrazide Formation

A compound of structure VI or X (when R29 and R⁸ taken together is ═O)is reacted with excess amount of hydrazine to form a compound ofstructure VII or XI where R¹² is a hydrogen. Preferably the reaction iscarried out in refluxing solvents such as EtOH or MeOH for 1-8 hours.

Step E. Curtis Reaction

A compound of structure VII or XI is reacted with reagent such asisoamyl nitrite in the presence of acid to form a reactive intermediateisocyanate, which is followed by intramolecular cyclization to form acompound of structure VIII or XII where R¹² is hydrogen.

Step F. Appending Ring D

A compound of structure XII or XVI is reacted with a reactive carboxylderivatives (acid halide or ester) or the corresponding acids underamide coupling conditions to form a compound of general structure VIIIor XIII (Y═C=O). Alternatively, a compound of general structure XII canbe alkylated to form other compounds of general structure VIII.Alternatively, a compound of structure XII is reacted with reactivecarbonyl derivatives (aldehyde or ketone) under the reductive aminationcondition. Other methods include using alkylating agents such as alkylhalide, benzyl halide, mesylate, tosylate and the like. Generalconditions are described above.

Step F′.

Optionally, functional group manipulation of a compound of structureVIII may be done to provide additional related compounds of structureVIII.

Step G. Amidation of Ester

A suitable protected ester of structure VI or X where R29 and R⁸ takentogether is ═O and Pr¹ is alkyl, is reacted with a primary or secondaryamine to provide compounds of structure XII or XV. Typical conditionsinclude the reaction of the ester and the amine in a polar solvent suchas methanol in a sealed tube at 25° C. to 100° C.

Step I. Reduction of Ester

A suitably protected ester of structure VI where R29 and R⁸ takentogether is ═O and Pr¹ is alkyl, is reacted with reducing agent such asdiisopropyl aluminum hydride to provide a primary hydroxy compound ofstructure XIV where R29 and R⁸ are H. General conditions for thereduction are described above.

Step I′. Azide Formation

A primary hydroxy compound of structure VI where R¹═R²═H is reacted withazide forming agent such as diphenylphosphoryl azide to provide acompound of structure XIV. Typical conditions include that the alcoholis reacted with a base and an azide forming reagent in solvents such asmethylene chloride and toluene at 25° C.

Step J. Reduction of Azide

An azide of structure XIV where R29═R⁸=H is reduced to amine XII whereR¹=R²=H by hydrogenation in the presence of Pd/C catalyst. The reactionis carried out in the solvents such as MeOH, EtOH or the like at 25° C.under atmospheric pressure.

Step K. Reduction of Nitro Group

A compound of structure XX is reacted with a reducing agent such assodium borohydride to provide a compound of structure XXI. Generalconditions for reduction are described above.

Step H. Diamine Cyclization

A compound of structure XII, XV or XXI where R29=R⁸=H is reacted withactivated carbonyl or activated imine agents to provide the fusedbicyclic compounds of structure XIII, XVI or XXII. Typical conditionsinclude the reaction of the diamine and the activated carbonyl agentsuch as carbonyl diimidazole in a halogenated solvent such as methylenechloride at 25° C. to 100° C.

Step H′

Optionally, functional group manipulation of a compound of structure XIIor XXI may be done to provide additional related compounds of structureXIII or XXII.

Compounds of Formula 1 can be prepared by the general methods outlinedin Schemes 1, 2, 3, 4, and 5. Synthesis of the specifically exemplifiedcompounds was prepared as described in detailed below. The followingEXAMPLES are being provided to further illustrate the present invention.They are for illustrative purposes only; the scope of the invention isnot to be considered limited in any way thereby.

EXAMPLES

The following preparative examples are intended to illustrate, but notto limit, the scope of the invention.

Preparative Examples Preparative Example 1

A round bottomed flask was charged with methyl 6-amino 2,3-dichloropyrazine 5-carboxylate (Aldrich, 25 g, 112.6 mmol), 2-S-ethyl piperazine(prepared as per Williams et al J. Med. Chem 1996, 39, 1345, 83% active,15.7 g, 112.7 mmol), cesium carbonate (100 g, 300 mmol) and 1,4 dioxane(400 mL). The flask was equipped with a reflux condenser and heated to80° C. After 12 hours the reaction was cooled, diluted with CH₂Cl₂ (˜200mL), and filtered through celite. The filtrate was washed once withwater and then concentrated to an oil. The crude product was purified bysilica gel column chromatography (3% to 10% MeOH in CH₂Cl₂) to affordcompound A3 (30.8 g, 91%). MS: M+H=300.

Preparative Example 2

A flask was charged with the compound of structure A3 (6.0 g, 20.0mmol), N-Boc piperidine-4-one C2 (10.0 g, 50.2 mmol), and1,2-dichloroethane (100 mL). The reducing reagent NaB(OAc)₃H (1.5equivalents) was added slowly with stirring. The resulting suspensionwas allowed to stir at 25° C. for 7 days, then treated with 1.0 M sodiumsolution to pH=13, extracted with CH₂Cl₂, and dried over sodium sulfate.The solvent was then removed under reduced pressure and the residue waspurified by SiO₂ column chromatography (1.5% then 5.0% MeOH in CH₂Cl₂)to provide C3 as a gel (9.8 g, ˜100%). MS: M+H=483.

Preparative Example 3

A solution of C3 (5 g, 10.3 mmol) in ethanol (100 mL) was treated withHydrazine (anhydrous, 4 ml, 127 mmol) at 25° C., and the reactionmixture was stirred at reflux for 22 hours. The reaction mixture wascooled and concentrated in vacuo to provide crude D1. Furtherpurification was carried out using SiO₂ flash column chromatography (5%MeOH in CH₂Cl₂) to afford the desired product D1 (3.06 g, 61% yield).MS: M+H=483.

Preparative Example 4

A solution of D1 (1.2 g, 2.5 mmol) in 2-methoxyethanol (32 mL) wastreated with 6 N HCl in isopropyl alcohol (1.6 mL) and isoamyl nitrite(0.35 ml, 2.6 mmol) at 25° C. The reaction mixture was stirred for 0.5hours at the temperature and then heated up to 100° C. for 16 hours. Thereaction mixture was cooled and concentrated in vacuo to afford (1.1 g,91%) of crude product E1 as a HCl salt form which was used for nextreaction without further purification. MS: M+H=366 (for free base).

Preparative Example 5 Preparation of Table 1 Compound No. 12

A solution of E1 (hydrochloride salt, 30 mg, 0.074 mmol) in DMF (1 mL)was treated with lithium 2-amino-6-chloronicotinate (15 mg, 0.082 mmol,preparation: see below), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDCl, 28 mg, 0.15 mmol), and 1-hydroxybenzotriazole (30mg, 0.22 mmol) at 0° C. The reaction mixture was allowed to warm up to25° C. and stirred at the temperature for 16 hours. The reaction mixturewas diluted in EtOAc and washed with water. The organic solution waswashed with saturated aqueous NaHCO₃ solution, brine solution and driedover anhydrous sodium sulfate. After concentration, the residualmaterial was purified by SiO₂ column chromatography to afford thedesired product F1 (14.7 mg, 38%). MS: M+H=520.

Preparative Example 6 Preparation of Table 1 Compound No. 13

A mixture of E1 (hydrochloride salt form, 100 mg, 0.25 mmol) and sodiumiodide (4 mg, 0.025 mmol) in DMF (1 mL) was treated with triethylamine(0.1 ml, 0.75 mmol) and 2-cyano-4-chlorobenzyl bromide (0.11 ml, 0.5mmol) at 25° C. The reaction mixture was stirred for 3 hours at thetemperature and diluted in CH₂Cl₂. The organic solution was washed withsaturated aqueous NaHCO₃ solution, brine solution, dried over sodiumsulfate, and concentrated in vacuo. The residual material was purifiedby preparative TLC (10% MeOH in CH₂Cl₂) to afford the desired product F2(45 mg, 35%). MS: M+H=517.

Preparative Example 7 Preparation of Table 1 Compound No. 33

A solution of E1 (hydrochloride salt form, 172 mg, 0.43 mmol) andpotassium cyanide (56 mg, 0.86 mmol) in water (1 mL) was treated with2-3 drops of 1 N HCl at 25° C. The solution was slowly added to asolution of 4-chlorobenzaldehyde in CH₂Cl₂ (1 mL) at 0° C. The reactionmixture was diluted with methanol (2 mL) and stirred at 25° C. for 4days. The reaction mixture was poured into water and the organic layerswere extracted with EtOAc. The combined organic solution was washed withbrine solution, dried over sodium sulfate, and concentrated in vacuo.The residual material was purified by preparative TLC (10% MeOH inCH₂Cl₂) to afford the desired product F3 (117 mg, 53%) as a 1:1 mixtureof diastereoisomers. MS: M+H=515.

Preparative Example 8 Preparation of Table 1 Compound No. 2

A solution of D2 (82 mg, 0.16 mmol) in 2-methoxyethanol (2 mL) wastreated with 6 N HCl in isopropyl alcohol (0.1 mL) and isoamyl nitrite(23 μl, 0.17 mmol) at 25° C. The reaction mixture was stirred for 0.5hours at the temperature and then heated up to 100° C. for 16 hours. Thereaction mixture was cooled and concentrated in vacuo to afford thedesired product E2 (82 mg, 98%) as a HCl salt form which was pure enoughwithout further purification. MS: M+H=490 (for free base).

Preparative Example 9

An ester of structure C4 (20 mg, 0.04 mmol) was dissolved in 2 N ethylamine in MeOH (5 mL). The reaction mixture was heated to 65° C. for 18hours in a pressure vessel. The reaction mixture was cooled andconcentrated in vacuo. The residual material was purified by SiO₂ columnchromatography (3% to 10% MeOH in CH₂Cl₂) to afford the desired productG1 (18 mg, 88%). MS: M+H=520.

Preparative Example 10 Preparation of Table 1 Compound No. 20

A compound of structure of G1 (12 mg, 0.023 mmol) was dissolved in ethylorthoformate (1 mL) and acetic anhydride (1 mL). The reaction mixturewas stirred at 100° C. for 16 hours. The reaction mixture was cooled andconcentrated in vacuo. The residual material was dissolved in CH₂Cl₂ andthe organic solution was washed with saturated aqueous NaHCO₃ solution,brine solution, dried over sodium sulfate, and concentrated in vacuo.Purification by preparative TLC (10% MeOH in CH₂Cl₂) afforded thedesired product H1 (6 mg, 50%). MS: M+H=530.

Preparative Example 11

A solution of compound C3 (0.75 g, 1.55 mmol) in MeOH (10 mL) wastreated with ethylene diamine (1.57 ml, 233 mmol) at 25° C. The reactionmixture was stirred at 70° C. for 16 hours in a sealed tube. Thereaction mixture was cooled and concentrated in vacuo. The residualmaterial was purified by SiO₂ column chromatography (2% MeOH in CH₂Cl₂to a mixture of CH₂Cl₂/MeOH/NH₄OH, 94/5/1) to afford the desired productG2 (510 mg, 64%). MS: M+H=511.

Preparative Example 12

A solution of compound G2 (175 mg, 0.34 mmol) in CHCl₃ (2 mL) wastreated with carbonyl diimidazole (61 mg, 0.37 mmol) at 25° C. Thereaction mixture was stirred at the temperature for 16 hours. Thereaction mixture was concentrated in vacuo and the residual material wasdissolved in CH₂Cl₂ (5 mL). The solution was treated withtrifluoroacetic acid (0.5 mL) at 0° C., and the reaction mixture wasstirred for 3 hours at 25° C. The reaction mixture was concentrated invacuo and the residual material was purified by SiO₂ columnchromatography (CH₂Cl₂/MeOH/NH₄OH=93/5/2 to 88/10/2) to afford thedesired product H2 (33 mg, 22%). MS: M+H=437.

Preparative Example 13 Preparation of Table 1 Compound No. 34

A solution of H2 (30 mg, 0.068 mmol) in DMF (2 mL) was treated withlithium 2-amino-6chloronicotinate (18 mg, 0.102 mmol, preparation: seebelow), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 38 mg, 0.10 mmol), and triethylamine (95 μl,0.68 mmol) at 25° C. The reaction mixture was stirred at the temperaturefor 16 hours. The reaction mixture was diluted in EtOAc and washed withwater. The organic solution was washed with brine solution and driedover anhydrous sodium sulfate. After concentration, the residualmaterial was purified by preparative TLC (CH₂Cl₂/MeOH/NH₄OH=93/5/2) toafford the desired product F4 (3.5 mg, 8.8%). MS: M+H=591.

Preparative Example 14

Compound C5 (1.74 g, 3.30 mmol) was dissolved in anhydrous THF (30 mL)and was cooled to −78° C. with a dry ice acetone bath. DIBAL (1 M, 11.6ml, 11.6 mmol) was added dropwise through a syringe. After the reactionmixture was stirred at −78° C. for 1 hour, saturated aqueous sodiumpotassium tartrate solution was added. The reaction mixture was allowedto warm up to 25° C. and stirred for 0.3 hours. The aqueous layer wasextracted with EtOAc. The organic solution was dried over anhydroussodium sulfate, filtered, and concentrated to dryness. The crude productwas purified by silica gel chromatography (5% MeOH in CH₂Cl₂) to givethe desired compound I1 (1.40 g. 85%). MS: M+H=497.

Preparative Example 15

Compound I1 (210 mg, 0.422 mmol) was dissolved in a mixture of anhydrousCH₂Cl₂ and anhydrous toluene (1:1, 7 mL). Diphenylphosphoryl azide(0.096 ml, 0.443 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,0.070 ml, 0.464 mmol) was added. After the reaction mixture was stirredat 25° C. for 12 hours, it was concentrated to dryness. The crudeproduct was purified by silica gel column chromatography (2.5% MeOH inCH₂Cl₂) to give compound 12 (170 mg, 77%). MS: M+H=522.

Preparative Example 16

Compound I2 (170 mg, 0.325 mmol) and triphenylphosphine (110 mg, 0.422mmol) were dissolved in THF (2 mL). Water (5 drops) was added. Thereaction mixture was stirred at 25° C. 16 hours. The reaction mixturewas concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (5% MeOH in CH₂Cl₂) to afford the desired compoundJ1 (156 mg, 97%). MS: M+H=496

Preparative Example 17 Preparation of Table 1 Compound No. 4

Compound J1 (48.0 mg, 0.097 mmol) and N,N′-carbonyl diimidazole (16 mg,0.097 mmol) were dissolved in CHCl₃ (1 mL). After the reaction mixturewas stirred at 25° C. for 10 minutes, it was heated to reflux for 2hours. After cooling, the solvent was concentrated to dryness, and thecrude product was purified by silica gel column chromatography (2.5%MeOH in CH₂Cl₂) to give the desired compound H3 (40 mg, 79%). MS:M+H=522.

Preparative Example 18

Compound J1 (82.5 mg, 0.177 mmol) and3,4-diethoxy-3-cyclobutene-1,2-dione (30.7 mg, 0.177 mmol) weredissolved in EtOH (2 mL). The reaction mixture was stirred at 25° C. for12 hours. The solvent was evaporated to dryness and, the crude productwas purified by silica gel column chromatography (2.5% MeOH in CH₂Cl₂)to give the desired compound J2 (80.8 mg, 75%). MS: M+H=620

Preparative Example 19 Preparation of Table 1 Compound No. 1

Compound J2 (16 mg, 0.025 mmol), N,N-diisopropylethylamine (2 drop) andEtOH were added to a pressure tube. The tube was sealed and heated to130° C. for 2 days. After cooling, the solvent was concentrated todryness. The crude product was purified by preparative TLC (5% MeOH inCH₂Cl₂) to give the desired compound H4 (3.8 mg, 26%). MS: M+H=574.

Preparative Example 20

The commercially available N-(4,5-Dichloro-2-nitro-phenyl)-acetamide A4(1.4 g, 5.6 mmol) was mixed with (S)-ethylpiperazine HCl salt A2 (1 g,4.7 mmol), K₂CO₃ (5 g, 37 mmol), catalytic Kl in N,N-dimethylformamide.The mixture was heated at 90° C. for 16 hours and solvent was removed.After aqueous workup, the crude product was purified by silica gelcolumn chromatography to afford the desired product A5 (1.03 g, 79%).MS: M+H=327.

Preparative Example 21

A compound of structure A5 (500 mg, 1.53 mmol) and1-(4-Chloro-2-fluoro-benzyl)-piperidin-4-one C6 were dissolved in 3%HOAc/DMF and sodium triacetoxyborohydride (650 mg, 3 mmol) was added.The reaction mixture was stirred for 16 hours at 25° C. After aqueousworkup, the crude product was purified by silica gel columnchromatography to yield the desired compound C7 (750 mg, 96%). MS:M+H=510.

Preparative Example 22

A compound of structure C7 (330 mg, 0.65 mmol) was dissolved in absoluteEtOH. Sodium borohydride (123 mg, 3.25 mmol) and cobalt chloride (85 mg,0.65 mmol) was slowly added and the mixture was heated at 85° C. for 45minutes. The reaction was then quenched by water. After aqueous workup,the crude product was purified by silica gel column chromatography togive the desired product K1 (260 mg, 83%). MS: M+H=480.

Preparative Example 23 Preparation of Table 1 Compound No. 10

A compound of structure K1 (10 mg, 0.02 mmol) and 1 ml oftrifluoroacetic acid were added in a pressure vessel and the reactionmixture was heated at 90° C. for 16 hours. Solvent was removed and thecrude product was purified by preparative HPLC to yield the desiredcompound H5 (8 mg, 73%). MS: M+1=558.

Preparative Example 24 Preparation of Table 1 Compound No. 21

A compound of structure K1 (8.4 mg, 0.018 mmol) was dissolved in THF (1mL). 1,1′-carbonyldiimidazole (20 mg, 0.12 mmol) and triethylamine (0.1mL) were added and the reaction mixture was stirred at 25° C. for 16hours. Solvent was removed and the crude product was purified bypreparative HPLC to yield the desired compound H6 (6 mg, 88%). MS:M+H=506,

Preparative Example 25 Preparation of Table 1 Compound No. 5

Preparation of Table 1 Compound No. 5 was prepared by the same methodshown for Preparative Examples 14 through 17. MS: M+H=547.

Preparative Example 26 Preparation of Table 1 Compound No. 16

Preparation of Table 1 Compound No. 16 was prepared by the same methodshown for Preparative Examples 14 through 17. MS: M+H=523.

Preparative Example 27 Preparation of Table 1 Compound No. 3

Preparation of Table 1 Compound No. 3 was prepared by the same methodshown for Preparative Examples 3 through 6. MS: M+H=521.

Preparative Example 28 Preparation of Table 1 Compound No. 6

Preparation of Table 1 Compound No. 6 was prepared by the same methodshown for Preparative Example 8. MS: M+H=509.

Preparative Example 29 Preparation of Table 1 Compound No. 11

Preparation of Table 1 Compound No. 11 was prepared by the same methodshown for Preparative Examples 3 through 6. MS: M+H=521.

Preparative Example 30 T Preparation of Table 1 Compound No. 14

Preparation of Table 1 Compound No. 14 was prepared by the same methodshown for Preparative Examples 3 through 6. MS: M+H=549.

Preparative Example 31 Preparation of Table 1 Compound No. 17

Preparation of Table 1 Compound No. 17 was prepared by the same methodshown for Preparative Examples 3 through 6. MS: M+H=523.

Preparative Example 32 Preparation of Table 1 Compound No. 7

Preparation of Table 1 Compound No. 7 was prepared by the same methodshown for Preparative Examples 9 through 10. MS: M+H=533.

Preparative Example 33 Preparation of Table 1 Compound No. 15

Preparation of Table 1 Compound No. 15 was prepared by the same methodshown for Preparative Examples 9 through 10. MS: M+H=577.

Preparative Example 34 Preparation of Table 1 Compound No. 9

Preparation of Table 1 Compound No. 9 was prepared by the same methodshown for Preparative Examples 20 through 23. MS: M+H=559.

Lithium 2-amino-5-chloronicotinate

A solution of 2,5-dichloronicotinic acid (20.2 g, 0.105 mol) in methanol(500 mL) was cooled to 0° C. and neat thionyl chloride (38 mL, 63 g,0.525 mol) was added over ˜30 min. The reaction mixture was stirred at0° C. for 1 hour. The cooling bath was removed, the reaction temperaturewas allowed to warm to room temperature, and the reaction was allowed tostir for an additional 2 days at room temperature. The solvent wasremoved under reduced pressure to give an off-white residue. The residuewas dissolved in Et₂O (˜500 mL) and the resulting solution was washedsuccessively with saturated aqueous NaHCO₃ solution (˜300 mL), water(˜300 mL), and brine (˜300 mL). The organic layer was separated, driedover anhydrous MgSO₄, and filtered. Removal of the solvent under reducedpressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97%) as a whitesolid.

Performed in duplicate on identical scales in two pressure vessels,methyl 2,5-dichloronicotinate (4.5 g, 22 mmol) was dissolved in ammoniasolution (250 mL, 0.5 M in 1,4-dioxane; 0.125 mol). The pressure vesselswere sealed and heated at (85±5)° C. for 9 days. The two reactionmixtures were allowed to cool to rt, then combined and concentratedunder reduced pressure to yield a white solid. Dissolution of the solidin 1:1 acetone-MeOH (˜500 mL), followed by adsorption onto silica gel(25 g) and then purification by flash column chromatography (25:10:1hexane-CH₂Cl₂-Et₂O), gave 6.08 g (75%) of methyl2-amino-5-chloronicotinate.

A solution of LiOH.H₂O (1.38 g, 33 mmol) in water (33 mL) was added inone portion to a suspension of methyl 2-amino-5-chloronicotinate (6.08g, 27 mmol) in MeOH (110 mL). The reaction mixture was stirred at 70° C.for 24 hours, and gradually became homogeneous. The solvents wereremoved under reduced pressure, and after the resulting white solid wasdried under vacuum (<1 mmHg) to constant weight, 5.51 g (95%) of lithium2-amino-5-chloronicotinate was obtained.

Biological Examples

The inventive compounds can readily be evaluated to determine activityat the CXCR3 receptors by known methods, such as, for example,development of a human CXCR3 (N-delta 4) Binding Assay.

Cloning and Expression of Human CXCR3 (N-delta 4):

The DNA encoding human CXCR3 was cloned by PCR using human genomic DNA(Promega, Madison, Wis.) as a template. The PCR primers were designedbased on the published sequence of human orphan receptor GPR9 (1) withincorporated restriction sites, a Kozak consensus sequence, CD8 leaderand Flag tag. The PCR product was subcloned into the mammalianexpression vector pME18Sneo, a derivative of the SR-alpha expressionvector (designated as pME18Sneo-hCXCR3 (N-delta 4).

IL-3-dependent mouse pro-B cells Ba/F3 were transfected byelectroporation in 0.4 ml Dulbecco's PBS containing 4×10⁶ cells with 20μg of pME18Sneo-hCXCR3 (N-delta 4) plasmid DNA. Cells were pulsed at 400Volts, 100 OHMs, 960 pFd. The transfected cells were under selectionwith 1 mg/ml G418 (Life Technologies, Gaithersburg, Md.). G418-resistantBa/F3 clones were screened for CXCR3 expression by specific binding of[¹²⁵I] IP10 (NEN Life Science Products, Boston, Mass.).

Preparation of Ba/F3-hCXCR3 (N-delta 4) Membranes:

Ba/F3 cells expressing human CXCR3 (N-delta 4) were pelleted andresuspended in the lysis buffer containing 10 mM HEPES, pH 7.5 andComplete® protease inhibitors (1 tablet per 100 ml) (BoehringerMannheim, Indianapolis, Ind.) at a cell density of 20×10⁶ cells per ml.After 5 minute incubation on ice, cells were transferred to 4639 celldisruption bomb (Parr Instrument, Moline, Ill.) and applied with 1,500psi of nitrogen for 30 minutes on ice. Large cellular debris was removedby centrifugation at 1,000×g. Cell membrane in the supernatant wassedimented at 100,000×g. The membrane was resuspended in the lysisbuffer supplemented with 10% sucrose and stored at −80° C. Total proteinconcentration of the membrane was determined by BCA method from Pierce(Rockford, Ill.).

Human CXCR3 (N-delta 4) Scintillation Proximity Assay (SPA):

For each assay point, 2 μg of membrane was preincubated for 1 hr with300 μg wheat germ agglutinin (WGA) coated SPA beads (Amersham, ArlingtonHeights, Ill.) in the binding buffer (50 mM HEPES, 1 mM CaCl₂, 5 mMMgCl₂, 125 mM NaCl, 0.002% NaN₃, 1.0% BSA) at room temperature. Thebeads were spun down, washed once, resuspended in the binding buffer andtransferred to a 96-well Isoplate (Wallac, Gaithersburg, Md.). 25 pM of[¹²⁵I] IP-10 with tested compounds in a series of titration were addedto start the reaction. After 3 hr reaction at room temperature, theamount of [¹²⁵I] IP10 bound to the SPA beads was determined with aWallac 1450 Microbeta counter.

The Ki ratings for the various compounds of the present invention aregiven in the afore-mentioned Table 1. From these ratings and valueranges, it would be apparent to the skilled artisan that the compoundsof the invention have excellent utility as CXCR3 receptor antagonists.

While the present invention has been describe in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, medications and variations are intendedto fall within the spirit and scope of the present invention.

1. A compound selected from the group consisting of: Compound NumberSTRUCTURE 13

14

15

16

17

18

19

20

22

23

26

30

33

34

and 38

or a pharmaceutically acceptable salt thereof.
 2. A compound selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 3. A compound accordingto claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising at least one compound of claim 1, or apharmaceutically acceptable salt thereof, in combination with at leastone pharmaceutically acceptable carrier.
 5. The pharmaceuticalcomposition of claim 4, further comprising at least one additionalagent, drug, medicament, antibody and/or inhibitor for treating a CXCR3chemokine receptor mediated disease.
 6. A pharmaceutical compositioncomprising at least one compound of claim 2, or a pharmaceuticallyacceptable salt thereof, in combination with at least onepharmaceutically acceptable carrier.
 7. The pharmaceutical compositionof claim 6, further comprising at least one additional agent, drug,medicament, antibody and/or inhibitor for treating a CXCR3 chemokinereceptor mediated disease.